Beta-amyloid protein production/secretion inhibitors

ABSTRACT

Provided are novel compounds having an inhibitory activity against production or secretion of β-amyloid protein. They embrace compounds represented by the following formula (1):  
                 
and capable of being replaced with a variety of substituents; and salts thereof, and solvates of any one of them.

TECHNICAL FIELD

The present invention relates to novel compounds having an inhibitoryactivity against production or secretion of β-amyloid protein; and amedicament to treat for various diseases caused by abnormal productionor secretion of β-amyloid protein such as Alzheimer disease, Downsyndrome and the other diseases associated with amyloid deposition.

BACKGROUND ART

Alzheimer disease is a neurodegenerative disease having pathologicalfeatures such as degeneration or loss of nerve cells, formation ofsenile plaques and neurofibrillary tangles. Alzheimer disease causessymptoms of dementia such as gradual loss of memory, recognition,thinking, judgment or the like, and it eventually leads to death. Noeffective method for treating or preventing this disease has hithertobeen known.

The main protein constituting a senile plaque deposited in the brain isβ-amyloid protein which is composed of from 39 to 43 amino acids.β-Amyloid protein exhibits cytotoxicity, which is presumed to induceAlzheimer disease (Science, 259, 514 (1993)). β-Amyloid protein secretedfrom cells is a polypeptide composed mainly of 40 or 42 amino acids andparticularly, that composed of 42 amino acids is known to deposit in thebrain quickly because of strong aggregation property and in addition,have strong cytotoxicity (Journal of Biological Chemistry, 270, 7013(1995)). β-Amyloid protein is produced ubiquitously in vivo, but itsfunction remains unknown.

β-Amyloid protein is produced by processing of a β-amyloid precursorprotein (APP) which is a membrane protein. Mutation of an APP gene isobserved from patients suffering from familial Alzheimer disease. Anincrease in the production or secretion amount of β-amyloid protein isknown to occur in the cells having this mutated gene introduced therein.This suggests that a medicament inhibiting the production or secretionof β-amyloid protein is effective for the prevention or treatment ofAlzheimer disease.

In the processing of APP, BACE (β-site APP Cleaving Enzyme) (Science,286, 735 (1999)) or Asp1 (Molecular and Cellular Neuroscience, 16, 609(2000)), each an aspartic protease, is reported as a β secretase forcleaving the N terminal of β-amyloid protein. It is suggested stronglythat presenilin participates in C-terminal cleavage events byγ-secretase (Nature, 398, 513 (1999)). Inhibitors of the secretase havebeen reported (Journal of Medicinal Chemistry, 44, 2039 (2001)), butmost of the inhibitors are peptide compounds.

In WO00/50391, SMITH, et al., disclose compounds having a sulfonamideskeleton and capable of controlling production of β-amyloid protein. InWO01/70677 (GB 026827) BELANGER, et al., disclose compounds having abicycloalkylsulfonamide skeleton and inhibiting γ-secretase.

An object of the present invention is to provide compounds having astructure different from that of the above-described known compounds,having excellent inhibitory action against production or secretion ofβ-amyloid protein and having desirable properties as pharmaceuticals.

DISCLOSURE OF THE INVENTION

The present inventors have carried out various investigations. As aresult, it has been found that thiomethane, sulfinylmethane or compoundsrepresented by the below-described formula (1) have excellent inhibitoryaction against production or secretion of β-amyloid protein and aretherefore useful as a medicament for treatment of various diseasesresulting from the abnormal production or secretion of β-amyloidprotein, leading to the completion of the present invention.

In the present invention, there is thus provided a compound representedby the following formula (1):

{wherein:

-   X represents —S—, —SO— or —SO₂—;-   R¹ represents:-   —C(R⁵)(R⁶)(R⁷)    -   [in which, R⁵, R⁶ and R⁷ each independently represents a halogen        atom, cyano group, nitro group or -Q⁵¹-Q⁵²-Q⁵³-Q⁵⁴    -   [in which, Q⁵¹ represents a single bond, —CO—, —CS—, —SO—,        —SO₂—, —CO—CO—, —CO—CS—, —CS—CO— or —CS—CS—,    -   Q⁵² represents a single bond, —O—, —O—N(A⁵¹)-, —O—N(COA⁵¹)-,        —N(A⁵¹)-, —N(COA⁵¹)-, —N(COOA⁵¹)-, —N(CON(A⁵¹)(A⁵²)-, —N(OA⁵¹)-,        —N(NA⁵¹A⁵²)-, —N(A⁵¹)-N(A⁵²)-, —N(COA⁵¹)-N(A⁵²)-, —N(A⁵¹)-O—,        —N(COA⁵¹)-O—, —S—, —N═N—, —C(A⁵¹)═N—, —C(A⁵¹)═N—O—,        —C(A⁵¹)═N—N(A⁵²)-, —N═C(A⁵¹)-, —O—N═C(A⁵¹)-, —(NA⁵¹)-N═C(A⁵²)-        or —C(═NA⁵¹)-N(A⁵²)-    -   (in which, A⁵¹ and A⁵² each independently represents a hydrogen        atom, a hydrocarbon group which may have a substituent or a        heterocyclic group which may have a substituent),    -   Q⁵³ represents a single bond, —CO—, —CS—, —SO—, —SO₂—, —CO—CO—,        —CO—CS—, —CS—CO— or —CS—CS—,    -   Q⁵⁴ represents -A⁵³, —OA⁵³, —N(A⁵³)(A⁵⁴), —SA⁵³, —NA⁵⁴-OA⁵³,        —NA⁵⁵-N(A⁵³)(A⁵⁴) or —O—N(A⁵³)(A⁵⁴)    -   (in which, A⁵³, A⁵⁴ and A⁵⁵ each independently represents a        hydrogen atom, a hydrocarbon group which may have a substituent        or a heterocyclic group which may have a substituent)], or    -   R⁵ and R⁶ may be coupled together to form a cyclic hydrocarbon        group which may have a substituent or a heterocyclic group which        may have a substituent (when the cyclic hydrocarbon group or        heterocyclic group formed by coupling of R⁵ and R⁶ is        unsaturated, R⁷ may represent the corresponding unsaturated        bond)], —N(R⁸)(R⁹)    -   [in which, R⁸ and R⁹ each independently represents        -Q⁸¹-Q⁸²-Q⁸³-Q⁸⁴    -   [in which, Q⁸¹ represents a single bond, —CO—, —CS—, —SO—,        —SO₂—, —CO—CO—, —CO—CS—, —CS—CO— or —CS—CS—,    -   Q⁸² represents a single bond, —O—, —O—N(A⁸¹)-, —O—N(COA⁸¹)-,        —N(A⁸¹)-, —N(COA⁸¹)-, —N(COOA⁸¹)-, —N(CON(A⁸¹)(A⁸²))-,        —N(OA⁸¹)-, —N(NA⁸¹A⁸²)-, —N(A⁸¹)-N(A⁸²)-, —N(COA⁸¹)-N(A⁸²)-,        —N(A⁸¹)-O—, —N(COA⁸¹)-O—, —S—, —N═N—, C(A⁸¹)═N—, —C(A⁸¹)═N—O—,        —C(A⁸¹)═N—N(A⁸²)-, —N═C(A⁸¹)-, —O—N═C(A⁸¹)-, —(NA⁸¹)-N═C(A⁸²)-        or —C(═NA⁸¹)-N(A⁸²)-    -   (in which, A⁸¹ and A⁸² each independently represents a hydrogen        atom, a hydrocarbon group which may have a substituent or a        heterocyclic group which may have a substituent),    -   Q⁸³ represents a single bond, —CO—, —CS—, —SO—, —SO₂—, —CO—CO—,        —CO—CS—, —CS—CO— or —CS—CS—,    -   Q⁸⁴ represents -A⁸³, —OA⁸³, —N(A⁸³)(A⁸⁴), —SA⁸³, —NA⁸⁴-OA⁸³,        —NA⁸⁵-N(A⁸³)(A⁸⁴) or —O—N(A⁸³)(A⁸⁴)    -   (in which, A⁸³, A⁸⁴ and A⁸⁵ each independently represents a        hydrogen atom, a hydrocarbon group which may have a substituent        or a heterocyclic group which may have a substituent)]],-   —X¹R¹⁰    -   [in which, X¹ represents —O— or —S— and R¹⁰ represents        -Q¹⁰¹-Q¹⁰²-Q¹⁰³-Q¹⁰⁴,    -   [in which, Q¹⁰¹ represents a single bond, —CO—, —CS—, —SO—,        —SO₂—, —CO—CO—, —CO—CS—, —CS—CO— or —CS—CS—,    -   Q¹⁰² represents a single bond, —O—, —O—N(A¹⁰¹)-, —O—N(COA¹⁰¹)-,        —N(A¹⁰¹)-, —N(COA¹⁰¹)-, —N(COOA¹⁰¹)-, —N(CON(A¹⁰¹)(A¹⁰²))-,        —N(OA¹⁰¹)-, —N(NA¹⁰¹A¹⁰²)-, —N(A¹⁰¹)-N(A¹⁰²)-,        —N(COA¹⁰¹)-N(A¹⁰²)-, —N(A¹⁰¹)-O—, —N(COA¹⁰¹)-O—, —S—, —N═N—,        —C(A¹⁰¹)═N—, —C(A¹⁰¹)═N—O—, —C(A¹⁰¹)═N—N(A¹⁰²)-, —N═C(A¹⁰¹)-,        —O—N═C(A¹⁰¹)-, —(NA¹⁰¹)-N═C(A¹⁰²)- or —C(═NA¹⁰¹)-N(A¹⁰²)-    -   (in which, A¹⁰¹ and A¹⁰² each independently represents a        hydrogen atom, a hydrocarbon group which may have a substituent        or a heterocyclic group which may have a substituent),    -   Q¹⁰³ represents a single bond, —CO—, —CS—, —SO—, —SO₂—, —CO—CO—,        —CO—CS—, —CS—CO— or —CS—CS—,    -   Q¹⁰⁴ represents -A¹⁰³, —OA¹⁰³, —N(A¹⁰³)(A¹⁰⁴), SA¹⁰³,        —NA¹⁰⁴-OA¹⁰³, —NA¹⁰⁵-N(A¹⁰³)(A¹⁰⁴) or —O—N(A¹⁰³)(A¹⁰⁴)    -   (in which, A¹⁰³, A¹⁰⁴ and A¹⁰⁵ each independently represents a        hydrogen atom, a hydrocarbon group which may have a substituent        or a heterocyclic group which may have a substituent)]], or-   —X²R¹¹    -   [in which, X² represents —SO— or —SO₂— and R¹¹ represents        -Q¹¹¹-Q¹¹²-Q¹¹³-Q¹¹⁴,    -   [in which, Q¹¹¹ represents a single bond, —CO—, —CS—, —SO—,        —SO₂—, —CO—CO—, —CO—CS—, —CS—CO— or —CS—CS—,    -   Q¹¹² represents a single bond, —O—, —O—N(A¹¹¹)-, —O—N(COA¹¹¹)-,        —N(A¹¹¹)-, —N(COA¹¹¹)-, —N(COOA¹¹¹)-, —N(CON(A¹¹¹)(A¹¹²))-,        —N(OA¹¹¹)-, —N(NA¹¹¹A¹¹²)-, —N(A¹¹¹)-N(A¹¹²)-,        —N(COA¹¹¹)-N(A¹¹²)-, —N(A¹¹¹)-O—, —N(COA¹¹¹)-O—, —S—, —N═N—,        —C(A¹¹¹)═N—, —C(A¹¹¹)═N—O—, —C(A¹¹¹)═N—N(A¹²)-, —N═C(A¹¹¹)-,        —O—N═C(A¹¹¹)-, —(NA¹¹¹)-N═C(A¹¹²)- or —C(═NA¹¹¹)-N(A¹¹²)-    -   (in which, A¹¹¹ and A¹¹² each independently represents a        hydrogen atom, a hydrocarbon group which may have a substituent        or a heterocyclic group which may have a substituent),    -   Q¹¹³ represents a single bond, —CO—, —CS—, —SO—, —SO₂—, —CO—CO—,        —CO—CS—, —CS—CO— or —CS—CS—,    -   Q¹¹⁴ represents -A¹¹³, —OA¹¹³, —N(A¹¹³)(A¹¹⁴), —SA¹¹³,        —NA¹¹⁴-OA¹¹³, —NA¹¹⁵-N(A¹¹³)(A¹¹⁴) or —O—N(A¹¹³)(A¹¹⁴)    -   (in which, A¹¹³, A¹¹⁴ and A¹¹⁵ each independently represents a        hydrogen atom, a hydrocarbon group which may have a substituent        or a heterocyclic group which may have a substituent)]];-   R² represents -Q²¹-Q²²-Q²³-Q²⁴    -   [in which, Q²¹ represents a single bond, —CO—, —CS—, —SO—,        —SO₂—, —CO—CO—, —CO—CS—, —CS—CO— or —CS—CS—,    -   Q²² represents a single bond, —O—, —O—N(A²¹)-, —O—N(COA²¹)-,        —N(A²¹)-, —N(COA²¹)-, —N(COOA²¹)-, —N(CON(A²¹)(A²²))-,        —N(OA²¹)-, —N(NA²¹A²²)-, —N(A²¹)-N(A²²)-, —N(COA²¹)-N(A²²)-,        —N(A²¹)-O—, —N(COA²¹)-O—, —S—, —N═N—, C(A²¹)═N—, —C(A²¹)═N—O—,        —C(A²¹)═N—N(A²²)-, —N═C(A²¹)-, —O—N═C(A²¹)-, —(NA²¹)-N═C(A²²)-        or —C(═NA²¹)-N(A²²)-    -   (in which, A²¹ and A²² each independently represents a hydrogen        atom, a hydrocarbon group which may have a substituent or a        heterocyclic group which may have a substituent),    -   Q²³ represents a single bond, —CO—, —CS—, —SO—, —SO₂—, —CO—CO—,        —CO—CS—, —CS—CO— or —CS—CS—,    -   Q²⁴ represents -A²³, —OA²³, —N(A²³)(A²⁴), —SA²³, —NA²⁴-OA²³,        —NA²⁵-N(A²³)(A²⁴) or —NA²⁵-N(A²³)(A²⁴)    -   (in which, A²³, A²⁴ and A²⁵ each independently represents a        hydrogen atom, a hydrocarbon group which may have a substituent        or a heterocyclic group which may have a substituent)]; or-   R¹ and R² may be coupled together to form a cyclic hydrocarbon group    which may have a substituent or a heterocyclic group which may have    a substituent, or may be coupled together to form ═CR¹²R¹³    -   [in which, R¹² and R¹³ each independently represents a halogen        atom, cyano group, nitro group or -Q¹²¹-Q¹²²-Q¹²³-Q¹²⁴,    -   [in which, Q¹²² represents a single bond, —CO—, —CS—, —SO—,        —SO₂—, —CO—CO—, —CO—CS—, —CS—CO— or —CS—CS—,

Q¹²² represents a single bond, —O—, —O—N(A¹²¹)-, —O—N(COA¹²¹)-,—N(A¹²¹)-, —N(COA¹²¹)-, N(COOA¹²¹)-, —N(CON(A¹²¹)(A¹²²))-, —N(OA¹²¹)-,—N(NA¹²¹A¹²²)-, —N(A¹²¹)-N(A¹²²)-, —N(COA¹²¹)-N(A¹²²)-, —N(A¹²¹)-O—,—N(COA¹²¹)-O—, —S—, —N═N—, —C(A¹²¹)═N—, —C(A¹²¹)═N—O—,—C(A¹²¹)═N—N(A¹²²)-, —N═C(A¹²¹)-, —O—N═C(A¹²¹)-, —(NA¹²¹)-N═C(A¹²²)- or—C(═NA¹²¹)-N(A¹²²)-

-   -   (in which, A¹²¹ and A¹²² each independently represents a        hydrogen atom, a hydrocarbon group which may have a substituent        or a heterocyclic group which may have a substituent),    -   Q¹²³ represents a single bond, —CO—, —CS—, —SO—, —SO₂—, —CO—CO—,        —CO—CS—, —CS—CO— or —CS—CS—,    -   Q¹²⁴ represents -A¹²³, —OA¹²³, —N(A¹²³)(A¹²⁴), —SA¹²³,        —NA¹²⁴-OA¹²³, —NA¹²⁵-N(A¹²³)(A¹²⁴) or —O—N(A¹²³)(A¹²⁴)    -   (in which, A¹²³, A¹²⁴ and A¹²⁵ each independently represents a        hydrogen atom, a hydrocarbon group which may have a substituent        or a heterocyclic group which may have a substituent)]];

-   R³ represents -Q³¹-Q³²-Q³³-Q³⁴,    -   [in which, Q³¹ represents a single bond, —CO—, —CS—, —SO—,        —SO₂—, —CO—CO—, —CO—CS—, —CS—CO— or —CS—CS—,    -   Q³² represents a single bond, —O—, —O—N(A³¹)-, —O—N(COA³¹)-,        —N(A³¹)-, —N(COA³¹)-, —N(COOA³¹)-, —N(CON(A³¹)(A³²))-,        —N(OA³¹)-, —N(NA³¹A³²)-, —N(A³¹)-N(A³²)-,        —N(COA³¹)-N(A³²)-N(A³¹)-O—, —N(COA³)-O—, —S—, —N═N—, —C(A³¹)═N—,        —C(A³)═N—O—, —C(A³¹)═N—N(A³²)-, —N═C(A³¹)-, —O—N═C(A³¹)-,        —(NA³¹)-N═C(A³²)- or —C(═NA³¹)-N(A³²)-    -   (in which, A³¹ and A³² each independently represents a hydrogen        atom, a hydrocarbon group which may have a substituent or a        heterocyclic group which may have a substituent),    -   Q³³ represents a single bond, —CO—, —CS—, —SO—, —SO₂—, —CO—CO—,        —CO—CS—, —CS—CO— or —CS—CS—,    -   Q³⁴ represents -A³³, —OA³³, —N(A³³)(A³⁴), —SA³³, —NA³⁴-OA³³,        —NA³⁵-N(A³³)(A³⁴) or —O—N(A³³)(A³⁴)    -   (in which, A³³, A³⁴ and A³⁵ each independently represents a        hydrogen atom, a hydrocarbon group which may have a substituent        or a heterocyclic group which may have a substituent)];

-   R⁴ represents -Q⁴¹-Q⁴²-Q⁴³-Q⁴⁴,    -   [in which, Q⁴¹ represents a single bond, —CO—, —CS—, —SO—,        —SO₂—, —CO—CO—, —CO—CS—, —CS—CO— or —CS—CS—,    -   Q⁴² represents a single bond, —O—, —O—N(A⁴¹)-, —O—N(COA⁴¹)-,        —N(A⁴¹)-, —N(COA⁴¹)-, —N(COOA⁴¹)-, —N(CON(A⁴¹)(A⁴²))-,        —N(OA⁴¹)-, —N(NA⁴¹A⁴²)-, —N(A⁴¹)-N(A⁴²)-, —N(COA⁴¹)-N(A⁴²)-,        —N(A⁴¹)-O—, —N(COA⁴¹)-O—, —S—, —N═N—, —C(A⁴¹)=═N—, —C(A⁴¹)═N—O—,        —C(A⁴¹)═N—N(A⁴²)-, —N═C(A⁴¹)-, —O—N═C(A⁴¹)-, —(NA⁴¹)-N═C(A⁴²)-        or —C(═NA⁴¹)-N(A⁴²)-    -   (in which, A⁴¹ and A⁴² each independently represents a hydrogen        atom, a hydrocarbon group which may have a substituent or a        heterocyclic group which may have a substituent),    -   Q⁴³ represents a single bond, —CO—, —CS—, —SO—, —SO₂—, CO—CO—,        —CO—CS—, —CS—CO— or —CS—CS—,    -   Q⁴⁴ represents -A⁴³, —OA⁴³, —N(A⁴³)(A⁴⁴), —SA⁴³, —NA⁴⁴-OA⁴³,        —NA⁴⁵-N(A⁴³)(A⁴⁴) or —O—N(A⁴³)(A⁴⁴)    -   (in which, A⁴³, A⁴⁴ and A⁴⁵ each independently represents a        hydrogen atom, a hydrocarbon group which may have a substituent        or a heterocyclic group which may have a substituent)]; or

-   R³ and R⁴ may be coupled together to form a cyclic hydrocarbon group    which may have a substituent or a heterocyclic group which may have    a substituent}, N-oxide or S-oxide of the compound, salt thereof, or    solvate of the above-described compound.

In the present invention, there is also provided a medicamentcontaining, as an effective ingredient, the compound represented by theformula (1), N-oxide or S-oxide thereof, or salt thereof, or solvate ofthereof.

In the present invention, there is also provided a pharmaceuticalcomposition containing the compound represented by the formula (1),N-oxide or S-oxide thereof, or salt thereof, or solvate of thereof; anda pharmaceutically acceptable carrier.

In the present invention, there is also provided use of the compoundrepresented by the formula (1), N-oxide or S-oxide thereof, or saltthereof, or solvate of thereof for the preparation of a medicament.

In the present invention, there is also provided a method of treating adisease resulting from abnormal production or secretion of β-amyloidprotein, which comprises administering an effective amount of thecompound represented by the formula (1), N-oxide or S-oxide thereof, orsalt thereof, or solvate of thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

A description will next be made of the compound represented by theformula (1).

The term “hydrocarbon group” as used herein means a group composed onlyof carbon and hydrogen atoms. The group may be any one of linear,branched and cyclic, or a combination of any two or three of them and itmay be either one of saturated and unsaturated groups.

Typical examples of the linear or branched hydrocarbon group includealkyl, alkenyl and alkynyl groups, and combinations thereof. Theselinear or branched hydrocarbon groups embrace those having a pluralityof double bonds or triple bonds, or those having both a double bond andtriple bond.

As the alkyl group, linear or branched alkyl groups having from 1 to 18carbon atoms, especially linear or branched alkyl groups having from 1to 12 carbon atoms are preferred. Specific examples of such an alkylgroup include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, 2-methylpentyl, 2-ethylpentyl, n-hexyl,n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-decyl groups.

As the alkenyl group, linear or branched alkenyl groups having from 2 to18 carbon atoms, especially linear or branched alkenyl groups havingfrom 2 to 12 carbon atoms are preferred. Specific examples of such analkenyl group include vinyl, allyl, propenyl, butenyl and pentenylgroups.

As the alkynyl group, linear or branched alkynyl groups having from 2 to18 carbon atoms, especially linear or branched alkynyl groups havingfrom 2 to 12 carbon atoms are preferred. Specific examples of such analkynyl group include ethynyl, 2-butynyl and 3-pentynyl groups.

Typical cyclic hydrocarbon groups include cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, spiro-hydrocarbon, crosslinked cyclic hydrocarbon,and condensed polycyclic hydrocarbon groups. A combination thereof isalso usable. The cyclic hydrocarbons groups embrace those having aplurality of double bonds or triple bonds and those having both a doublebond and a triple bond.

Examples of the cycloalkyl group include cycloalkyl groups having from 3to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

Examples of the cycloalkenyl group include cycloalkenyl groups havingfrom 4 to 7 carbon atoms such as cyclopentenyl and cyclohexenyl.Examples of the cycloalkynyl group include cycloalkynyl groups havingfrom 4 to 7 carbon atoms.

Examples of the aryl group include monocyclic or polycyclic aromatichydrocarbon groups having from 6 to 14 carbon atoms. Specific examplesinclude phenyl, indenyl, naphthyl, anthracenyl and biphenyl.

Examples of the spiro-hydrocarbon group include spiro-hydrocarbon groupshaving from 7 to 11 carbon atoms such as spiro[3.4]octanyl andspiro[4.5]deca-1,6-dienyl groups.

Examples of the crosslinked cyclic hydrocarbon group include crosslinkedcyclic hydrocarbon groups having from 7 to 10 carbon atoms such asbicyclo[2.2.1]heptanyl, adamantyl, bicyclo[3.2.1]octanyl,bicyclo[2.2.1]hept-2-enyl, tricyclo[2.2.1.0^(2,6)]heptanyl andbicyclo[4.3.1]decanyl groups.

Examples of the condensed polycyclic hydrocarbon group include condensedpolycyclic hydrocarbon groups having from 8 to 14 carbon atoms such asindanyl, tetrahydronaphthalenyl, hexahydroindanyl andoctahydronaphthalenyl groups.

The term “heterocyclic group” as used herein means a cyclic group havingone or more hetero atoms (N, O, S, etc.) as a component of its cyclicstructure and it may be any one of a saturated ring, an unsaturated ringor aromatic ring, or may be either one of a monocyclic or polycyclicgroup. It also embraces a group introduced from a heterocyclic spirocompound or a heterocyclic compound having a crosslinked cyclicstructure.

Examples of the saturated monocyclic heterocyclic group include from 3-to 7-membered groups each having from 1 to 4 atoms selected fromnitrogen, oxygen and sulfur atoms. Specific examples includepyrrolidinyl, tetrahydrofuranyl, oxetanyl, tetrahydrothienyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxiranyl,thioranyl, dioxanyl, aziridinyl, imidazolidinyl, pyrazolidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroxazolyl,tetrahydrothiazolyl, tetrahydroisoxazolyl, tetrahydroisothiazolyl,dioxolanyl and oxathioranyl groups.

Examples of the unsaturated monocyclic heterocyclic group include from4- to 7-membered groups having 1 to 4 atoms selected from nitrogen,oxygen and sulfur atoms. Specific examples include pyrrolyl, furyl,thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, dihydrooxazolyl, dihydrothiazolyl,dihydroisoxazolyl, dihydroisothiazolyl, pyridyl, pyrimidinyl, triazinyl,tetrazolyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiadiazolyl,oxadiazolyl, dihydroxazolyl, dihydrothiazolyl, dihydroisoxazolyl,dihydroisothiazolyl, pyrazinyl, pyridazinyl, pyranyl, dihydropyridinyl,dihydropyrrolyl, dihydroquinolyl, dihydroimidazolyl, dihydropyrazolyl,dihydropyrazinyl and dihydropyridazinyl groups.

Examples of the polycyclic heterocyclic group include from 7- to14-membered groups having 1 to 4 atoms selected from nitrogen, oxygenand sulfur atoms. Specific examples include benzofuranyl,benzothiazolyl, indolyl, quinolyl, isoquinolyl, benzopyranyl,benzoxazolyl, benzothiazolyl, benzimidazolyl, benzodioxanyl,benzothiophenyl, benzisothiazolyl, benzisoxazolyl, chromenyl, chromanyl,isochromenyl, isochromanyl, indolinyl, indazolyl, indolizinyl,isoindolyl, isoindolinyl, quinolizinyl, quinoxalinyl, quinazolyl,cinnolinyl, phthalazinyl, naphthyridinyl, purinyl, carbazolyl,xanthenyl, acridinyl, phenazinyl, phenoxazinyl, phenothiazinyl andquinuclidinyl groups.

Examples of the combination of cycloalkyl and alkyl groups includecycloalkyl-alkyl groups, with (C₃₋₇ cycloalkyl)-(C₁₋₁₂ alkyl) groupsbeing especially preferred.

As the combination of aryl and alkyl groups, (C₆₋₁₀ aryl)-(C₁₋₁₂ alkyl)groups are preferred.

Examples of the substituent for these hydrocarbon groups andheterocyclic groups include -Q²⁰¹-Q²⁰²-Q²⁰³-Q²⁰⁴-Q²⁰⁵-Q²⁰⁶-Q²⁰⁷, inwhich Q²⁰¹ represents a single bond, an alkyl group having from 1 to 6carbon atoms, an alkenyl group having from 2 to 6 carbon atoms orheterocyclic group; Q²⁰² represents a single bond, —O—, —NH—, —CH═—N—,—C(alkyl)═N—, —N(alkyl)- or —S—; Q²⁰³ represents a single bond, —CO—,—CS—, —SO—, —SO₂— or —CONH—; Q²⁰⁴ represents a single bond, an alkylgroup from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6carbon atoms, a cycloalkyl group, a cycloalkenyl group, an aromatichydrocarbon group or a heterocyclic group; Q²⁰⁵ represents a singlebond, —O—, —NH— or —N(alkyl)-; Q²⁰⁶ represents a single bond, —CO—, CS—,—SO₂—, —SO— or —S—; and Q²⁰⁷ represents a hydrogen atom, a halogen atom,a hydroxy group, an oxo group, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₃₋₈ cycloalkyl group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group,an azide group, a cyano group, an amino group, a C₁₋₆ alkylamino group,a di(C₁₋₆ alkyl)amino group, a C₂₋₆ alkanoylamino group, di(C₂₋₆alkanoyl)amino group, a carboxyamino group, a C₁₋₆ alkoxycarbonylaminogroup, a di(C₁₋₆ alkoxy)carbonylamino group, a heterocyclic group, anaromatic hydrocarbon group, a cycloalkenyl group, a heterocyclic oxygroup, or an aromatic hydrocarbon-oxy group. The alkyl group having from1 to 6 carbon atoms, alkenyl group having from 2 to 6 carbon atoms,cycloalkyl group, cycloalkenyl group, heterocyclic group,heterocyclic-oxy group, aromatic hydrocarbon group or aromatichydrocarbon-oxy group may be substituted with 1 to 3 substituentsselected from halogen atoms, C₁₋₆ alkyl groups, C₁₋₆ alkoxy groups, C₂₋₆alkenyl groups, carboxyamino(C₁₋₆ alkyl) groups, (C₁₋₆alkoxy)carbonylamino(C₁₋₆ alkyl) groups, formyl group, C₂₋₆ alkanoylgroups, oxo group, nitro group, cyano group, azide group, amidino group,C₂₋₆ alkenyloxy groups, hydroxy group, carboxyl group, C₇₋₁₆ aralkylgroups, thioxo group, C₂₋₇ alkanoyl groups, C₂₋₇ thioalkanoyl groups,thioformyl group, amino group, C₁₋₆ alkylamino groups, di(C₁₋₆alkyl)amino groups, C₁₋₆ alkoxycarbonyl groups, carbamoyl group, C₁₋₆alkylcarbamoyl groups, di(C₁₋₆ alkyl)carbamoyl groups, thiocarbamoylgroup, C₁₋₆ alkylthiocarbamoyl groups, di(C₁₋₆ alkyl)thiocarbamoylgroups, C₁₋₆ alkoxycarbamoylamino groups, C₁₋₆ alkoxycarbamoyl(C₁₋₆alkyl)amino groups, C₂₋₇ alkanoylamino groups, (C₂₋₇ alkanoyl)(C₁₋₆alkyl)amino groups, thio(C₂₋₇ alkanoyl)amino groups, thio(C₂₋₇alkanoyl)(C₁₋₆ alkyl)amino groups, formylamino group, formyl(C₁₋₆alkyl)amino groups, thioformylamino group, thioformyl(C₁₋₆ alkyl)aminogroups, C₂₋₇ alkanoyloxy groups, formyloxy group, C₁₋₆ alkoxycarbonyloxygroups, carbamoyloxy group, C₁₋₆ alkylcarbamoyloxy groups, di(C₁₋₆alkyl)carbamoyloxy groups, aminocarbonylamino group, (C₁₋₆alkyl)aminocarbonylamino groups, di(C₁₋₆ alkyl)aminocarbonylaminogroups, aminocarbonyl(C₁₋₆ alkyl)amino groups, (C₁₋₆alkyl)aminocarbonyl(C₁₋₆ alkyl)amino groups, di(C₁₋₆alkyl)aminocarbonyl(C₁₋₆ alkyl)amino groups, mercapto group, C₁₋₆alkylthio groups, C₁₋₆ alkylsulfinyl groups, C₁₋₆ alkylsulfonyl groups,aminosulfonyl group, C₁₋₆ alkylaminosulfonyl groups, di(C₁₋₆alkyl)aminosulfonyl groups, C₁₋₆ alkylsulfonylamino groups, (C₁₋₆alkylsulfonyl(C₁₋₆ alkyl)amino groups, aminosulfonylamino group, C₁₋₆alkylaminosulfonylamino groups, di(C₁₋₆ alkyl)aminosulfonylamino groups,aminosulfonyl(C₁₋₆ alkyl)amino groups, C₁₋₆ alkylaminosulfonyl(C₁₋₆alkyl)amino groups, and di(C₁₋₆ alkyl)aminosulfonyl(C₁₋₆ alkyl)aminogroups.

Examples of the aromatic hydrocarbon groups include C₆₋₁₄ aromatichydrocarbon groups, for example, phenyl, naphthyl, indenyl, anthracenyland biphenyl groups. Of these, phenyl and naphthyl groups are especiallypreferred. The heterocyclic groups include the above-described saturatedor unsaturated, monocyclic or polycyclic heterocyclic groups, forexample, pyrrolidinyl, tetrahydrofuranyl, oxetanyl, tetrahydrothienyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxiranyl,thiolanyl, dioxanyl, pyrrolyl, aziridinyl, imidazolidinyl,pyrazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydroisoxazolyl,tetrahydroisothiazolyl, dioxolanyl, oxathiolanyl, furyl, thienyl,pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, dihydroxazolyl, dihydrothiazolyl, dihydroisoxazolyl,dihydroisothiazolyl, pyridyl, pyrimidinyl, triazinyl, tetrazolyl,pyrrolinyl, imidazolinyl, pyrazolinyl, thiadiazolyl, oxadiazolyl,dihydrooxazolyl, dihydrothiazolyl, dihydroisoxazolyl,dihydroisothiazolyl, pyrazinyl, pyridazinyl, pyranyl, dihydropyridinyl,dihydropyrrolyl, dihydroquinolyl, dihydroimidazolyl, dihydropyrazolyl,dihydropyrazinyl, dihydropyridazinyl, benzofuranyl, benzothiazolyl,indolyl, quinolyl, isoquinolyl, benzopyranyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzodioxanyl, benzothiophenyl,benzisothiazolyl, benzisoxazolyl, chromenyl, chromanyl, isochromenyl,isochromanyl, indolinyl, indazolyl, indolizinyl, isoindolyl,isoindolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, naphthyridinyl, purinyl, carbazolyl, xanthenyl, acridinyl,phenazinyl, phenoxazinyl, phenothiazinyl and quinuclidinyl groups. Ofthese pyrrolidinyl, tetrahydrofuranyl, oxetanyl, tetrahydrothienyl,piperidinyl, dihydrooxazolyl, dihydrothiazolyl, dihydroisoxazolyl,dihydroisothiazolyl, piperazinyl, morpholinyl, thiomorpholinyl,oxiranyl, dioxanyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl,triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazinyl, tetrazolyl, benzofuranyl, benzothiophenyl,indolyl, quinolyl, isoquinolyl, benzopyranyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzodioxanyl, dioxolanyl,tetrahydropyranyl, tetrahydrothiopyranyl, oxadiazolyl, thiadiazolyl,pyrazinyl, pyridazinyl, dihydropyridinyl, dihydropyrrolyl,dihydroquinolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyrazinyl,dihydropyridazinyl, tetrahydrooxazolyl, chromenyl, chromanyl,isochromenyl, and isochromanyl groups are preferred, with pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolanyl,pyridyl, furyl and thienyl groups being especially preferred.

In the formula (1), X represents any one of —S—, —SO— and —SO₂—. Ofthese, —SO— are —SO₂— are preferred, with —SO₂— being especiallypreferred.

In the formula (1), R¹ represents any one of —C(R⁵)(R⁶)(R⁷), —N(R⁸)(R⁹),—X¹R¹⁰, and —X²R¹¹. Of these, R¹ representing —C(R⁵)(R⁶)(R⁷) ispreferred. Especially, R¹ representing —C(R⁵)(R⁶)(R⁷) in which R⁵ and R⁶may be coupled together to form a cyclic hydrocarbon group which mayhave a substituent or a heterocyclic group which may have a substituentis preferred.

In the formula (1), R² represents -Q²¹-Q²²-Q²³-Q²⁴, with R² representing-Q²¹-Q²²-Q²³-Q²⁴ in which Q²¹, Q²², and Q²³ each represents a singlebond and Q²⁴ represents A²³ in which A²³ represents a hydrogen atom oran alkyl group being preferred.

Or, R¹ and R² may be coupled together to form a cyclic hydrocarbon groupwhich may have a substituent, a heterocyclic group which may have asubstituent, or ═C(R¹²)(R¹³).

In the formula (1), R³ represents -Q³¹-Q³²-Q³³-Q³⁴, with R³ representing-A³³, —CO-A³³ or —COOA³³ in which A³³ represents a hydrogen atom, ahydrocarbon group which may have a substituent or a heterocyclic groupwhich may have a substituent being preferred.

R⁴ represents -Q⁴¹-Q⁴²-Q⁴³-Q⁴⁴-, with R⁴ representing -A⁴³ in which A⁴³represents a cyclic hydrocarbon group which may have a substituent or aheterocyclic group which may have a substituent being preferred.

In the present invention, compounds of the formula (1) in which R³represents a heterocyclic group which may have a substituent, R²represents a hydrogen atom or a C₁₋₆ alkyl group, R³ represents a cyclichydrocarbon group which may have a substituent or a heterocyclic groupwhich may have a substituent, and R⁴ represents a cyclic hydrocarbongroup which may have a substituent or a heterocyclic group which mayhave a substituent are especially preferred. These compounds arerepresented by the following formula (3):

(wherein, R¹⁵ represents a heterocyclic group which may have asubstituent, R¹⁶ represents a cyclic hydrocarbon group which may have asubstituent or a heterocyclic group which may have a substituent, R¹⁷represents a cyclic hydrocarbon group which may have a substituent or aheterocyclic group which may have a substituent, R¹⁸ represents ahydrogen atom or a C₁₋₆ alkyl group and X represents —S—, —SO— or—SO₂—).

As the heterocyclic group represented by R¹⁵, R¹⁶ or R¹⁷, theabove-described heterocyclic groups can be given as examples. As thecyclic hydrocarbon group represented by R¹⁶ or R¹⁷, the above-describedcyclic hydrocarbon groups can be given as examples. As the substituentson these groups, the above-described ones can be given as examples. AsX, —SO— or —SO₂— is preferred, with —SO₂— being especially preferred.

As the heterocyclic group represented by R¹⁵, R¹⁶ or R¹⁷, from 3- to7-membered saturated or from 4- to 7-membered unsaturated monocyclicheterocyclic groups having from 1 to 4 atoms selected from nitrogenatom, oxygen atom and sulfur atom, and from 7- to 14-membered polycyclicheterocyclic groups having from 1 to 4 atoms selected from nitrogenatom, oxygen atom and sulfur atom are preferred.

As the cyclic hydrocarbon group represented by R¹⁶ or R¹⁷, cycloalkylgroups having from 3 to 7 carbon atoms, cycloalkenyl groups having from4 to 7 carbon atoms, monocyclic or polycyclic aromatic hydrocarbongroups having from 6 to 14 carbon atoms, spirohydrocarbon groups havingfrom 7 to 11 carbon atoms, crosslinked cyclic hydrocarbon groups havingfrom 7 to 10 carbon atoms and condensed polycyclic hydrocarbon groupshaving from 8 to 14 carbon atoms are preferred.

As the substituent for the cyclic hydrocarbon group or heterocyclicgroup of R¹⁵, R¹⁶ or R¹⁷, groups represented by the above-described-Q²⁰¹-Q²⁰²-Q²⁰³-Q²⁰⁴-Q²⁰⁵-Q²⁰⁶ can be given as examples.

As the cyclic hydrocarbon group represented by R¹⁶ or R¹⁷, monocyclic orpolycyclic aromatic hydrocarbon groups having from 6 to 14 carbon atomsare preferred, with phenyl, naphthyl, indenyl and anthracenyl groupsbeing more preferred, and a phenyl group being especially preferred.These hydrocarbon groups may have 1 to 3 substituents selected fromhalogen atoms, C₁₋₆ alkyl groups, C₁₋₆ alkoxy groups, C₂₋₆ alkenylgroups, formyl group, C₂₋₆ alkanoyl groups, carboxyl group, carboxyaminoC₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonylamino C₁₋₆ alkyl groups, oxogroup, nitro group, cyano group, amidino group, C₂₋₇ alkenyloxy groups,hydroxy group, thioxo group, amino group, C₁₋₆ alkylamino groups,di(C₁₋₆ alkyl)amino groups, C₁₋₆ alkoxycarbonyl groups, carbamoyl group,C₁₋₆ alkylcarbamoyl groups, di(C₁₋₆ alkyl)carbamoyl groups,thiocarbamoyl group, C₁₋₆ alkylthiocarbamoyl groups, di(C₁₋₆alkyl)thiocarbamoyl groups, mercapto group, C₁₋₆ alkylthio groups, C₁₋₆alkylsulfinyl groups and C₁₋₆ alkylsulfonyl groups.

Examples of the heterocyclic group represented by R¹⁶ or R¹⁷ includepyrrolidinyl, tetrahydrofuranyl, oxetanyl, tetrahydrothienyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxiranyl,thiolanyl, dioxanyl, pyrrolyl, aziridinyl, imidazolidinyl,pyrazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydroisoxazolyl,tetrahydroisothiazolyl, dioxolanyl, oxathiolanyl, furyl, thienyl,pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, dihydroxazolyl, dihydrothiazolyl, dihydroisoxazolyl,dihydroisothiazolyl, pyridyl, pyrimidinyl, triazinyl, tetrazolyl,pyrrolinyl, imidazolinyl, pyrazolinyl, thiadiazolyl, oxadiazolyl,dihydrooxazolyl, dihydrothiazolyl, dihydroisoxazolyl,dihydroisothiazolyl, pyrazinyl, pyridazinyl, pyranyl, dihydropyridinyl,dihydropyrrolyl, dihydroquinolyl, dihydroimidazolyl, dihydropyrazolyl,dihydropyrazinyl, dihydropyridazinyl, benzofuranyl, benzothiazolyl,indolyl, quinolyl, isoquinolyl, benzopyranyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzodioxanyl, benzothiophenyl,benzisothiazolyl, benzisoxazolyl, chromenyl, chromanyl, isochromenyl,isochromanyl, indolinyl, indazolyl, indolizinyl, isoindolyl,isoindolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, naphthyridinyl, purinyl, carbazolyl, xanthenyl, acridinyl,phenazinyl, phenoxazinyl, phenothiazinyl and quinuclidinyl groups. Ofthese pyrrolidinyl, tetrahydrofuranyl, oxetanyl, tetrahydrothienyl,piperidinyl, dihydrooxazolyl, dihydrothiazolyl, dihydroisoxazolyl,dihydroisothiazolyl, piperazinyl, morpholinyl, thiomorpholinyl,oxiranyl, dioxanyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl,triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazinyl, tetrazolyl, benzofuranyl, benzothiophenyl,indolyl, quinolyl, isoquinolyl, benzopyranyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzodioxanyl, dioxolanyl,tetrahydropyranyl, tetrahydrothiopyranyl, oxadiazolyl, thiadiazolyl,pyrazinyl, pyridazinyl, dihydropyridinyl, dihydropyrrolyl,dihydroquinolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyrazinyl,dihydropyridazinyl, tetrahydrooxazolyl, chromenyl, chromanyl,isochromenyl, and isochromanyl groups are preferred, withtetrahydropyranyl, piperidinyl, pyridyl and pyrimidinyl groups beingespecially preferred. These heterocyclic groups may have 1 to 3substituents selected from halogen atoms, C₁₋₆ alkyl groups, C₁₋₆ alkoxygroups, C₂₋₆ alkenyl groups, formyl group, C₂₋₆ alkanoyl groups,carboxyl group, carboxyamino C₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonylaminoC₁₋₆ alkyl groups, oxo group, nitro group, cyano group, amidino group,C₂₋₇ alkenyloxy groups, hydroxy group, thioxo group, amino group, C₁₋₆alkylamino groups, di(C₁₋₆ alkyl)amino groups, C₁₋₆ alkoxycarbonylgroups, carbamoyl groups, C₁₋₆ alkylcarbamoyl groups, di(C₁₋₆alkyl)carbamoyl groups, thiocarbamoyl group, C₁₋₆ alkylthiocarbamoylgroups, di(C₁₋₆ alkyl)thiocarbamoyl groups, mercapto group, C₁₋₆alkylthio groups, C₁₋₆ alkylsulfinyl groups and C₁₋₆ alkylsulfonylgroups.

Examples of the heterocyclic group represented by R¹⁵ includepyrrolidinyl, tetrahydrofuranyl, oxetanyl, tetrahydrothienyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxiranyl,thiolanyl, dioxanyl, pyrrolyl, aziridinyl, imidazolidinyl,pyrazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydroisoxazolyl,tetrahydroisothiazolyl, dioxolanyl, oxathiolanyl, furyl, thienyl,pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, dihydroxazolyl, dihydrothiazolyl, dihydroisoxazolyl,dihydroisothiazolyl, pyridyl, pyrimidinyl, triazinyl, tetrazolyl,pyrrolinyl, imidazolinyl, pyrazolinyl, thiadiazolyl, oxadiazolyl,dihydrooxazolyl, dihydrothiazolyl, dihydroisoxazolyl,dihydroisothiazolyl, pyrazinyl, pyridazinyl, pyranyl, dihydropyridinyl,dihydropyrrolyl, dihydroquinolyl, dihydroimidazolyl, dihydropyrazolyl,dihydropyrazinyl, dihydropyridazinyl, benzofuranyl, benzothiazolyl,indolyl, quinolyl, isoquinolyl, benzopyranyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzodioxanyl, benzothiophenyl,benzisothiazolyl, benzisoxazolyl, chromenyl, chromanyl, isochromenyl,isochromanyl, indolinyl, indazolyl, indolizinyl, isoindolyl,isoindolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, naphthyridinyl, purinyl, carbazolyl, xanthenyl, acridinyl,phenazinyl, phenoxazinyl, phenothiazinyl and quinuclidinyl groups whichmay be substituted with the above-described-Q²⁰¹-Q²⁰²-Q²⁰³-Q²⁰⁴-Q²⁰⁵-Q²⁰⁶-Q²⁰⁷. Of these groups, pyrrolidinyl,tetrahydrofuranyl, oxetanyl, tetrahydrothienyl, piperidinyl,dihydrooxazolyl, dihydrothiazolyl, dihydroisoxazolyl,dihydroisothiazolyl, piperazinyl, morpholinyl, thiomorpholinyl,oxiranyl, dioxanyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl,triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazinyl, tetrazolyl, benzofuranyl, benzothiophenyl,indolyl, quinolyl, isoquinolyl, benzopyranyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzodioxanyl, dioxolanyl,tetrahydropyranyl, tetrahydrothiopyranyl, oxadiazolyl, thiadiazolyl,pyperizinyl, pyridazinyl, dihydropyridinyl, dihydropyrrolyl,dihydroquinolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyrazinyl,dihydropyridazinyl, tetrahydrooxazolyl, chromenyl, chromanyl,isochromenyl, and isochromanyl groups are preferred, withtetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, pyridyl,pyrimidinyl, imidazolyl, thiazolyl, benzimidazolyl and chromenyl groupsbeing especially preferred. The heterocyclic group may be substitutedwith a halogen atom, C₁₋₆ alkyl group, C₁₋₆ alkoxy group, C₂₋₆ alkenylgroup, C₂₋₆ alkenyloxy group, hydroxy group, carboxyl group, carboxyC₁₋₆ alkyl group, C₁₋₆ alkoxycarbonyl C₁₋₆ alkyl group, C₁₋₆alkoxycarbonyl-C₂₋₆ alkenyl group, hydroxyl C₁₋₆ alkyl group, (C₆₋₁₄aromatic hydrocarbon)-sulfonyl C₁₋₆ alkyl group, heterocyclic-C₁₋₆alkylamino group, heterocyclic group, heterocyclic-C₁₋₆ alkyl group,C₆₋₁₄ aromatic hydrocarbon group, (C₆₋₁₄ aromatic hydrocarbon)(C₁₋₆alkyl) group, (C₆₋₁₄ aromatic hydrocarbon)thio C₁₋₆ alkyl group,azido-C₁₋₆ alkyl group, amino C₁₋₆ alkyl group, C₁₋₆ alkylamino C₁₋₆alkyl group, di C₁₋₆ alkylamino C₁₋₆ alkyl group, hydroxy(C₁₋₆alkylamino)(C₁₋₈ alkyl) group, C₁₋₆ alkoxy(C₁₋₆ alkyl)amino C₁₋₆ alkylgroup, (hydroxy C₁₋₆ alkyl)(C₁₋₆ alkoxy C₁₋₆ alkyl)amino C₁₋₆ alkylgroup, C₂₋₆ alkanoylamino C₁₋₆ alkyl group, (C₆₋₁₄ aromatic hydrocarbon)sulfonylamino C₁₋₆ alkyl group, (C₁₋₆ alkoxy)carbonylamino C₁₋₆ alkylgroup, carbamoylamino C₁₋₆ alkyl group, N-alkylcarbamoylamino C₁₋₆ alkylgroup, N,N-dialkylcarbamoylamino C₁₋₆ alkyl group, aminosulfonylaminoC₁₋₆ alkyl group, N-alkylsulfonylamino C₁₋₆ alkyl group,N,N-dialkylsulfonylamino C₁₋₆ alkyl group, (C₆₋₁₄ aromatichydrocarbon)(C₁₋₆ alkyl)amino group, heterocyclic C₁₋₆ alkylamino group,carbamoyloxy C₁₋₆ alkyl group, N-alkylcarbamoyloxy C₁₋₆ alkyl group,N,N-dialkylcarbamoyloxy C₁₋₆ alkyl group, (C₆₋₁₄ aromatichydrocarbon)-(C₁₋₆ alkyl)carbamoyloxy C₁₋₆ alkyl group, C₁₋₆alkoxycarbonyloxy-C₁₋₆ alkyl group, (C₆₋₁₄ aromatichydrocarbon)oxycarbonyloxy C₁₋₆ alkyl group, (C₆₋₁₄ aromatichydrocarbon)sulfonylamino-(C₁₋₆ alkanoyl)amino C₁₋₆ alkyl group, C₁₋₆alkoxycarbonylamino C₁₋₆ alkylamino group, amino C₁₋₆ alkylamino group,C₁₋₆ alkylamino C₁₋₆ alkylamino group, di(C₁₋₆ alkyl)amino C₁₋₆alkylamino group, carboxyamino(C₁₋₆ alkyl) group, C₁₋₆alkoxycarbonylamino C₁₋₆ alkyl group, C₁₋₆ alkylsulfonylamino C₁₋₆ alkylgroup, amino C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl group, N—(C₁₋₆alkyl)amino C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl group, N,N-di(C₁₋₆alkyl)amino C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl group, heterocycliccarbonyl group, heterocyclic carbonylamino group, (C₆₋₁₄ aromatichydrocarbon)carbonyl group, C₆₋₁₄ aromatic carbonylamino group,heterocyclic C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl group, heterocyclic C₂₋₆alkenylcarbonylamino C₁₋₆ alkyl group, C₆₋₁₄ aromatic hydrocarbonalkenylcarbonylamino C₁₋₆ alkyl group, C₆₋₁₄ aromatic hydrocarboncarbonylamino C₁₋₆ alkyl group, heterocyclic carbonylamino C₁₋₆ alkylgroup, C₁₋₆ alkoxyoxalylamino C₁₋₆ alkyl group, carbamoyl group, N—(C₁₋₆alkyl) carbamoyl group, N,N-di(C₁₋₆ alkyl) carbamoyl group, C₁₋₆alkyl-C₃₋₈ cycloalkylcarbamoyl group, C₃₋₈ cycloalkyl-C₁₋₆alkylcarbamoyl group, heterocyclic carbamoyl group, C₁₋₆ aromaticcarbamoyl group, heterocyclic carbonylhydrazonomethyl group, C₆₋₁₄aromatic hydrocarbon carbonylhydrazonomethyl group, C₁₋₆ alkylthio C₁₋₆alkylcarbamoyl group, C₁₋₆ alkylsulfinyl C₁₋₆ alkylcarbamoyl group, C₁₋₆alkylsulfonyl C₁₋₆ alkylcarbamoyl group, hydroxyaminocarbonyl group,hydrazinocarbonyl group or N—C₁₋₆ alkylhydrazinocarbonyl group,thioformylamino-(C₆₋₁₄ aromatic hydrocarbon)-thiocarbonylamino C₁₋₆alkyl group, thioformyl-C₁₋₆ alkylamino-C₆₋₁₄ aromatichydrocarbon-thiocarbonylamino C₁₋₆ alkyl group, formylamino-(C₆₋₁₄aromatic hydrocarbon)-carbonylamino(C₁₋₆ alkyl) group, formyl-C₁₋₆alkylamino-(C₆₋₁₄ aromatic hydrocarbon)-carbonylamino C₁₋₆ alkyl group,C₁₋₆ alkanoyl-heterocycle-carbonylamino C₁₋₆ alkyl group, di(C₂₋₆alkanoyl)amino C₁₋₆ alkyl group, di(C₁₋₆ alkoxycarbonyl)amino C₁₋₆ alkylgroup, C₁₋₆ alkyl-heterocycle-carbonyl group, C₃₋₇ cycloalkyl C₁₋₆alkylaminocarbonyl group, C₁₋₆ alkoxyaminocarbonyl group, (hydroxy)(C₁₋₆alkyl)aminocarbonyl group, (C₁₋₆ alkoxy)(C₁₋₆ alkyl)aminocarbonyl group,N′—C₁₋₆ alkylhydrazinocarbonyl group, N′,N′-di(C₁₋₆alkyl)hydrazinocarbonyl group, N,N′-di(C₁₋₆ alkyl)hydrazinocarbonylgroup, N,N′,N′-tri(C₁₋₆ alkyl)hydrazinocarbonyl group,N′-(heterocycle-carbonyl)-hydrazinocarbonyl group, formyl group,hydroxyimino group, C₁₋₆ alkoxyimino group, bis(C₁₋₆ alkoxy C₁₋₆ alkyl)amino C₁₋₆ alkyl group, hydroxy-C₁₋₆ alkyl-heterocyclic group, C₁₋₆alkoxy-C₁₋₆ alkyl-heterocyclic group, C₁₋₆ alkoxycarbonylamino C₁₋₆alkyl-heterocyclic group, amino(C₁₋₆ alkyl)-heterocyclic group, N—C₁₋₆alkylamino C₁₋₆ alkyl-heterocyclic group, N,N-di(C₁₋₆ alkyl)amino C₁₋₆alkyl-heterocyclic group, hydroxy-heterocyclic group, C₁₋₆alkoxy-heterocyclic group, carboxy-C₂₋₅ alkenyl group, or oxo group(wherein, the above-described C₆₋₁₄ aromatic hydrocarbon group orheterocyclic group may be substituted with a halogen atom, C₁₋₆ alkylgroup, C₁₋₆ alkoxy group, C₂₋₆ alkenyl group, formyl group, C₂₋₆alkanoyl group, carboxyl group, carboxyamino(C₁₋₆ alkyl) group, C₁₋₆alkoxycarbonylamino(C₁₋₆ alkyl) group, oxo group, nitro group, cyanogroup, amidino group, C₂₋₆ alkenyloxy group, hydroxy group, thioxogroup, amino group, C₁₋₆ alkylamino group, di(C₁₋₆ alkyl)amino group,amino(C₁₋₆ alkyl) group, C₁₋₆ alkoxycarbonyl group, carbamoyl group,C₁₋₆ alkylcarbamoyl group, di(C₁₋₆ alkyl)carbamoyl group, thiocarbamoylgroup, C₁₋₆ alkylthiocarbamoyl group, di(C₁₋₆ alkyl)thiocarbamoyl group,C₂₋₇ alkanoylamino group, C₂₋₇ alkanoyl(C₁₋₆ alkyl)amino group, thioC₁₋₇ alkanoylamino group, thio C₂₋₇ alkanoyl (C₁₋₆ alkyl)amino group,formylamino group, formyl(C₁₋₆ alkyl)amino group, thioformylamino group,thioformyl(C₁₋₆ alkyl)amino group, C₂₋₇ alkanoyloxy group, formyloxygroup, mercapto group, C₁₋₆ alkylthio group, C₁₋₆ alkylsulfinyl group,C₁₋₆ alkylsulfonyl group, aminosulfonyl group, C₁₋₆ alkylaminosulfonylgroup, di C₁₋₆ alkylaminosulfonyl group, C₁₋₆ alkylsulfonylamino groupor C₁₋₆ alkylsulfonyl(C₁₋₆ alkyl)amino group.

The compounds of the present invention represented by the formula (1)may have a stereoisomer or an enantiomer derived from an asymmetrichydrocarbon. Any one of the stereoisomer and enantiomer, and mixturethereof are all embraced in the present invention. The S-oxide of theinvention compound exists when the heterocyclic group contains a sulfuratom. Either one of a monoxide or dioxide is embraced in the S-oxide.

No particular limitation is imposed on the salt of the compound of thepresent invention represented by the formula (1) insofar as it is apharmaceutically acceptable salt. Specific examples of the salt includemineral acid salts such as hydrochloride, hydrobromide, hydroiodide,phosphate, nitrate and sulfate, benzoates, organic sulfonates such asmethanesulfonate, 2-hydroxyethanesulfonate and p-toluenesulfonate, andorganic carboxylates such as acetate, propanoate, oxalate, malonate,succinate, glutarate, adipate, tartrate, maleate, malate and mandelate.

When the compound represented by the formula (1) has an acid group, thesalt may be a salt of an alkali metal ion or alkaline earth metal ion.No particular limitation is imposed on the solvate insofar as it ispharmaceutically acceptable. Specific examples of it include hydratesand ethanol solvates.

Preparation processes of the compounds of the present inventionrepresented by the formula (1) will next be described.

The compounds of the present invention represented by the formula (1) orsalts thereof, or solvates thereof can be prepared using generally knownchemical preparation processes in combination. Typical synthesisprocesses will next be described.

Upon synthesis of each invention compound, a substituent such asnitrogen atom, hydroxyl group or carboxyl group which needs protectionmay be protected by a generally known protecting group which can beremoved as needed. The protecting group can be eliminated by the generalorganic chemical method if necessary.

The sulfide compound (1) having S as X can be prepared by thesubstitution of a thiol compound with carbon or addition of carbon tothe thiol compound (below-described formulas 2, 4 and 5).

The sulfinyl compound (1) having SO as X can be prepared by oxidizing asulfide compound (below-described formula 2).

The sulfonyl compound (1) having SO₂ as X may be prepared by condensinga sulfonyl compound (R¹ and/or R² and/or R³═H) with a substituent (R¹and/or R² and/or R³) or by oxidizing the sulfide compound (X representsS) or sulfinyl compound (X represents SO) (the below-described formulas1 and 2). It can also be prepared by substituting a sulfinic acidcompound with carbon or adding carbon to the sulfinic acid compound (thebelow-described formulas 3, 4 and 5). Use of these processes incombination may also be employed for the preparation.

The substituent portion of the compound (1) thus prepared can beconverted and have another structure. Described specifically, R¹ and/orR² and/or R³ and/or R⁴ can be substituted with another substituent in aknown manner.

For example, the compound (1) having, as R¹ and/or R² and/or R³ and/orR⁴, an alkyl group having a hydroxyl group protected with a vinyl orsilyl group can be converted into the corresponding hydroxyalkyl groupby deprotection in a conventional manner. Moreover, the hydroxyl groupportion can be introduced into a functional group such as ester,carbonate, carbamate, halogen or sulfonate in a known manner. Or, someof them can be introduced into a substituent such as hydrocarbon,alkoxy, amine, amide or sulfide or into a functional group in aconventional manner. Alternatively, a cyclic portion can be formed withthe other R¹, R², R³ or R⁴.

Various functional groups besides a hydroxyl group can be obtained bysuch conversion and the conversion method can be performed based on theknown technique. The reagent, solvent and reaction conditions known perse in the art may be employed for these conversion steps.Preparation Process of the Sulfonyl Compound (1: X═SO₂): Reaction Scheme1

For example, various compounds (1) different in R¹ can be prepared byreacting a compound (1) having a hydrogen atom as R¹ and SO₂ as X, whichcompound is known or can be prepared in a known manner, with anelectrophilic reagent in the presence of a base in an inert solvent. Inthis reaction, R¹ can be introduced as an independent substituent byutilizing an intramolecular reaction with the electrophilic reagent, butalternatively, a cyclic structure can be formed together with R² by anintermolecular reaction with R² having an electrophilic functional groupon its side chain.

Described specifically, the reaction is effected by adding the compound(1: R²═H, X═SO₂) and at least an equivalent amount of a base with atleast an equivalent amount of an electrophilic reagent in an inertsolvent.

The reaction temperature is usually from −78° C. to 200° C.

The reaction time is usually from 0.5 hour to 1 day.

Examples of the inert solvent which can be used in the above-describedreaction include ether solvents, halogen solvents, aromatic solvents,nitrile solvents and amide solvents. They may be used either singly orin combination of two or more. Of these, tetrahydrofuran,dimethoxyethane, diethyl ether, dimethylformamide and toluene and so onare preferred.

Examples of the electrophilic reagent usable in the above reactioninclude R¹—Y [in which, Y represents an eliminating group], carbonylcompounds (such as aldehyde, ketone, ester and amide), and epoxycompounds. Alternatively, R² containing Y, carbonyl group or epoxy groupmay be used as the electrophilic functional group.

Examples of the eliminating group represented by Y include halogen atoms(such as chlorine, bromine and iodine), alkylsulfonyloxy groups havingfrom 1 to 6 carbon atoms, which groups may be halogenated (such asmethanesulfonyloxy, ethanesulfonyloxy and trifluoromethanesulfonyloxy),and arylsulfonyloxy groups which have from 6 to 10 carbon atoms and mayhave a substituent. Substituents for the arylsulfonyloxy group include 1to 3 halogen atoms, alkyl groups which have from 1 to 6 carbon atoms andmay be halogenated, and alkoxy groups having from 1 to 6 carbon atoms.

Specific examples of the eliminating group include benzenesulfonyloxy,p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy and2-naphthalensulfonyloxy groups.

Examples of the base which can be used for the above reaction includealkyl lithiums (such as n-butyl lithium, sec-butyl lithium and t-butyllithium), hydrides of an alkali metal or alkaline earth metal (such aslithium hydride, sodium hydride, potassium hydride and calcium hydride),amides of an alkali metal or alkaline earth metal (such as lithiumamide, sodium amide, lithium diisopropylamide, lithiumdicyclohexylamide, lithium hexamethyldisilazide, sodiumhexamethyldisilazide, and potassium hexamethyldisilazide), loweralkoxides of an alkali metal or alkaline earth metal (such as sodiummethoxide, sodium ethoxide, and potassium t-butoxide), hydroxides of analkali metal, alkaline earth metal or silver (such as silver hydroxide,sodium hydroxide, potassium hydroxide, lithium hydroxide and bariumhydroxide), carbonates of an alkali metal, alkaline earth metal orsilver (sodium carbonate, potassium carbonate, cesium carbonate andsilver carbonate), bicarbonates of an alkali metal (such as sodiumbicarbonate and potassium bicarbonate), and silver oxide.

The sulfonyl compound (1: X═SO₂) can also be prepared by reacting thecompound (1) which has a hydrogen atom as R¹ and SO₂ as X and is knownor can be prepared in a known manner with 1 to 3 equivalents of R¹—OH inthe presence of a condensing agent in an inert solvent.

The reaction temperature is usually from −20° C. to 200° C., preferablyfrom 0° C. to 150° C.

The reaction time is usually from 0.5 hour to 3 days.

Examples of the inert solvent which can be used in the above-describedreaction include ether solvents, halogen solvents and aromatic solvents.They may be used either singly or in combination of two or more. Ofthese, tetrahydrofuran and toluene are preferred.

Examples of the condensing agent which can be used in the above reactioninclude any one of cyanomethylene trialkylphosphoranes (such ascyanomethylene trimethylphosphorane and cyanomethylenetri-n-butylphosphorane), triarylphosphines (such as triphenylphosphine)and trialkylphosphines (such as tributylphosphine), and azodicarboxylicacid compounds (such as diethyl azodicarboxylate, diisopropylazodicarboxylate, dipiperizineamide azodicarboxylate andbisdimethylamide azodicarboxylate).

Preparation Process of a Sulfonyl Compound (1: X═SO₂) having SR¹⁰ as R¹

The sulfonyl compound (1: X═SO₂) having SR¹⁰ as R¹ is available byreacting a compound (1), which has a hydrogen atom as R¹ and SO₂ as Xand is known or can be prepared in a known manner, with from 1 to 3equivalents or R¹⁰S—Y (Y has the same meaning as described above) in thepresence of from 1 to 3 equivalents of a base (such as sodium hydride)in an inert solvent.

The reaction temperature is usually from −20° C. to 150° C.

The reaction time is usually from 0.5 hour to 1 day.

Examples of the inert solvent which can be used in the above-describedreaction include ether solvents, halogen solvents, aromatic solvents,and amide solvents. They may be used either singly or in combination oftwo or more. Of these, dimethylformamide is preferred.

Preparation Process of a Sulfonyl Compound (1: X═SO₂) in which R¹ and R²have been Coupled Together to Form ═CR¹²R¹³

The sulfonyl compound (1: X—SO₂) in which R¹ and R² have been coupledtogether to form ═CR¹²R¹³ can be prepared by acting a base on a compound(1) having a hydrogen atom as R¹, SO₂ as X and —CYR¹²R¹³ [Y has the samemeaning as described above) as R².

More specifically, the compound which has a hydrogen atom as R², SO₂ asX and —CYR¹²R¹³ as R² [Y has the same meaning as described above] and isknown or available in a conventional manner is treated with at least anequivalent amount of a base in an inert solvent.

The reaction temperature is usually from −78° C. to 150° C., preferablyfrom −78° C. to 50° C. The reaction time is usually from 0.5 hour to 1day.

Examples of the inert solvent which can be used in the above-describedreaction include alcohol solvents, ether solvents, halogen solvents,aromatic solvents, nitrile solvents, amide solvents, ketone solvents,sulfoxide solvents and water. They may be used either singly or incombination of two or more. Of these, methylene chloride,tetrahydrofuran and diethyl ether and so on are preferred.

Examples of the base which can be used for the above reaction includehydrides of an alkali metal or alkaline earth metal (such as lithiumhydride, sodium hydride, potassium hydride and calcium hydride); amidesof an alkali metal or alkaline earth metal (such as lithium amide,sodium amide, lithium diisopropylamide, lithium dicyclohexylamide,lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassiumhexamethyldisilazide); lower alkoxides of an alkali metal or alkalineearth metal (such as sodium methoxide, sodium ethoxide, and potassiumt-butoxide); hydroxides of an alkali metal, alkaline earth metal orsilver (such as silver hydroxide, sodium hydroxide, potassium hydroxide,lithium hydroxide and barium hydroxide); carbonates of an alkali metal,alkaline earth metal or silver (sodium carbonate, potassium carbonate,cesium carbonate and silver carbonate); bicarbonates of an alkali metal(such as sodium bicarbonate and potassium bicarbonate); alkyl lithiums(such as n-butyl lithium) or alkyl Grignards (such as methyl magnesiumbromide); inorganic bases such as silver oxide or amines (such astriethylamine, diisopropylethylamine and N-methylmorpholine); andorganic bases, for example, basic heterocyclic compounds (such asdimethylaminopyridine, pyridine, imidazole, 2,6-lutidine, collidine,1,8-diazabicyclo[5.4.0]undece-7-en, 1,5-diazabicyclo[4.3.0]non-5-en, and1,4-diazabicyclo[2.2.2]octane).Preparation Process of a Sulfide Compound (1: X═S), a Sulfinyl Compound(1: X═SO), a Sulfonyl Compound (1: X═SO₂)

1) Preparation Process of the Sulfide Compound (1: X═S)

The compound (1) having S as X is available by reacting the compound (2)with a thiol compound in the presence of a base in an inert solvent.

The compound (2) having a hydroxyl group can be prepared in a knownmanner. Various processes are known and one example will next bedescribed. The compound (2) having a hydroxyl group is available byadding an organometal reagent (as a metal, lithium or magnesiumrepresentative of a Grignard reagent is usually employed) in an amountof from equivalent to excess to an aldehyde or ketone represented byR¹(C═O)R² in an inert solvent such as tetrahydrofuran or diethyl etherto react them. The organometal reagent represented by R³-M can beprepared, for example when R³ represents an aromatic ring or aromaticheterocycle, by adding an alkyl lithium reagent or alkyl Grignardreagent to an aryl halide to cause metal exchange, as reported in thepaper of H. Gilman, et. al., J. Org. Chem. 1951, 16, 1788-1791, or inthe paper of F. Trecourt, et al., Tetrahedron 2000, 56, 1349-1460. Thecompound (2) having an eliminating group Y can be prepared by convertingthe hydroxyl group of the hydroxyl-containing compound (2) to aneliminating group in a known manner.

The compound (1) having S as X is also obtainable by reacting thecompound (2) with an alkali metal or alkaline earth metal salt (such aslithium, sodium or potassium) of a thiol compound in an inert solvent.

The reaction temperature is usually from −20° C. to 200° C., preferablyfrom room temperature to 100° C. When the R substituent of the compoundis a bulky one, reaction at a temperature higher than the above one orreaction in a sealed tube is sometimes preferred.

The reaction time usually ranges from 0.5 hour to 1 hour.

Examples of the base which can be used in the above-described reactioninclude hydrides of an alkali metal or alkaline earth metal (such aslithium hydride, sodium hydride, potassium hydride and calcium hydride),amides of an alkali metal or alkaline earth metal (such as lithiumamide, sodium amide, lithium diisopropylamide, lithiumdicyclohexylamide, lithium hexamethyldisilazide, sodiumhexamethyldisilazide, and potassium hexamethyldisilazide), loweralkoxides of an alkali metal or alkaline earth metal (such as sodiummethoxide, sodium ethoxide, and potassium t-butoxide), hydroxides of analkali metal, alkaline earth metal or silver (such as silver hydroxide,sodium hydroxide, potassium hydroxide, lithium hydroxide and bariumhydroxide), carbonates of an alkali metal, alkaline earth metal orsilver (sodium carbonate, potassium carbonate, cesium carbonate andsilver carbonate), bicarbonates of an alkali metal (such as sodiumbicarbonate and potassium bicarbonate), alkyl lithiums (such as n-butyllithium) or alkyl Grignard reagents (such as methyl magnesium bromide),inorganic bases such as silver oxide, or amines (such as triethylamine,diisopropylethylamine and N-methylmorpholine), and organic bases, forexample, basic heterocyclic compounds (such as dimethylaminopyridine,pyridine, imidazole, 2,6-lutidine, collidine,1,8-diazabicyclo[5.4.0]undece-7-en, 1,5-diazabicyclo[4.3.0]non-5-en, and1,4-diazabicyclo[2.2.2]octane).

Examples of the inert solvent which can be used in the above-describedreaction include alcohol solvents, ether solvents, halogen solvents,aromatic solvents, nitrile solvents, amide solvents, ketone solvents,sulfoxide solvents and water. They may be used either singly or incombination of two or more. Of these, methylene chloride,tetrahydrofuran and diethyl ether are preferred.

The compound (2) has a hydroxyl group instead of the eliminating groupY, a condensate can be prepared by the Mitsunobu reaction.

The compound (1) can be prepared by reacting the hydroxyl-containingcompound (2) which is known or can be prepared in a known manner with 1to 3 equivalents of a thiophenol compound in the presence of both 1 to 3equivalents of a triarylphosphine (such as triphenylphosphine) ortrialkylphosphine (such as tributylphosphine) and 1 to 2 equivalents ofan azodicarboxylic acid compound (such as diethyl azodicarboxylate,diisopropyl azodicarboxylate, dipiperidineamide dicarboxylate orbisdimethylamide azodicarboxylate) in an inert solvent.

The reaction temperature is usually from −20° C. to 150° C., preferablyfrom room temperature to 80° C. When the R substituent of the compoundis a bulky one, reaction at a high temperature or reaction in a sealedtube is sometimes preferred.

The reaction time usually ranges from 0.5 hour to 1 day.

Examples of the inert solvent which can be used in the above-describedreaction include ether solvents, halogen solvents, and aromaticsolvents. Two or more of these solvents may be used as a mixture. Ofthese, tetrahydrofuran is preferred.

2) Preparation Process of the Sulfinyl Compound (1: X═SO)

The sulfinyl compound (1: X═SO) can be synthesized by oxidizing thesulfide compound (1: X═S), more specifically, reacting the sulfidecompound (1) in the presence of an oxidizing agent in an inert solvent.

The reaction temperature usually ranges from −20° C. to 200° C.,preferably from 0° C. to 100° C.

Examples of the inert solvent which can be used in the above reactioninclude alcohol solvents, ether solvents, halogen solvents, aromaticsolvents, nitrile solvents, amide solvents, ketone solvents, sulfoxidecompounds and water. Two or more of these solvents may be used incombination. Of these, methylene chloride, chloroform, methanol andethanol are preferred.

Examples of the oxidizing agent which can be used in the above reactioninclude hydrogen peroxide, organic peracid compounds (such as peraceticacid and meta-chloroperbenzoic acid), metaperiodates (such as sodiummetaperiodate), acyl nitrate, dinitrogen tetroxide, halogen, N-halogencompounds (such as N-chlorosuccinimide and N-bromosuccinimide),hydroperoxides (such as t-butylhydroperoxide), iodobenzene diacetate,iodobenzene dichloride, t-butyl hypochlorite, sulfuryl chloride, singletoxygen, ozone, selenium oxide, and seleninic acid. An optically activesulfoxide (1: X═SO) can be prepared by using titaniumtetraisopropoxide/diethyl tartrate/t-butylhydroperoxide, titaniumtetraisopropoxide/diethyl tartrate/peracetic acid or the like.

Described specifically, the sulfide compound (1: X═S) and from 1 to 2equivalents of an oxidizing agent such as meta-chloroperbenzoic acid,sodium periodate or hydrogen peroxide may be stirred in an inert solventsuch as methylene chloride, tetrahydrofuran-water, methanol or the likeat 0 to 100° C. for from about 1 hour to 2 days.

3) Preparation Process of the Sulfonyl Compound (1: X═SO₂)

The sulfonyl compound (1: X═SO₂) can be synthesized by oxidizing thesulfide compound (1: X═S) or sulfinyl compound (1: X═SO₂), morespecifically, by reacting the sulfide compound (1: X═S) or sulfinylcompound (1: X═SO) with an oxidizing agent in an inert solvent.

The reaction temperature usually ranges from −20° C. to 150° C.,preferably from 0° C. to 80° C.

Examples of the inert solvent which can be used in the above-describedreaction include alcohol solvents, ether solvents, halogen solvents,aromatic solvents, carboxylic acid solvents, nitrile solvents, amidesolvents, ketone solvents, sulfoxide solvents and water. Two or more ofthese solvents may be used as a mixture. Of these, methylene chloride,chloroform, methanol, ethanol and acetic acid are preferred.

Examples of the oxidizing agent which can be used in the above reactioninclude hydrogen peroxide, hydrogen peroxide—transition metal catalyst(such as ammonium molybdate or iron (III) chloride), organic peracidcompounds (such as peracetic acid and meta-chloroperbenzoic acid),metaperiodates (such as sodium metaperiodate), potassium peroxysulfate,permanganates (such as potassium permanganate), sodium perborate,halogen, N-halogen compounds (such as N-chlorosuccinimide andN-bromosuccinimide), hydroperoxides (such as t-butylhydroperoxide),iodobenzene diacetate, iodobenzene dichloride, hypochlorites (such assodium hypochlorite, or t-butyl hypochlorite), singlet oxygen, ozone,selenium oxide, and seleninic acid. The preferred example of thereaction conditions include reaction of the sulfide compound (1: X═S)with from 2 to 5 equivalents of an oxidizing agent (such asmeta-chloroperbenzoic acid, sodium periodate, hydrogen peroxide orhydrogen peroxide-ammonium molybdate) in methylene chloride,tetrahydrofuran-water or methanol at from 0 to 100° C. for from about 1hour to 2 days.Preparation Process of the Sulfonyl Compound (1: X═SO₂): Reaction Scheme3

The sulfonyl compound (1: X═SO₂) can be synthesized by introducing asulfonyl group into the compound (2), more specifically, by reacting thecompound (2) with an alkali metal, alkaline earth metal ortetrabutylammonium salt of sulfinic acid.

Described specifically, the compound (2) is reacted with from anequivalent to excess amount of sulfinic acid or salt thereof in an inertsolvent.

The reaction temperature usually ranges from −20° C. to 200° C.,preferably from room temperature to 100° C. When the R substituent ofthe compound is a bulky one, reaction at higher reaction temperaturethan that described above or reaction in a sealed tube is sometimespreferred.

The reaction time usually ranges from 0.5 hour to 1 day.

Examples of the inert solvent which can be used in the above reactioninclude alcohol solvents, ether solvents, halogen solvents, aromaticsolvents, nitrile solvents, amide solvents, ketone solvents, sulfoxidesolvents and water. Two or more of these solvents may be used as amixture. Of these, butanol and dimethoxyethane are preferred.Preparation Process of the Sulfide Compound (1: X═S): Reaction Scheme 4

Preparation Process of the Sulfide Compound (1: X═S) (1) when Y¹ or Y²is an Electron Attractive Group

The compound (1) can be prepared by subjecting the compound (4) which isknown or is available in a known manner to the Michael reaction, morespecifically, by reacting the compound (4) with a thiol (R⁴SH) in thepresence of a base.

Described specifically, the compound (4) is reacted with from anequivalent to excess amount of a thiol in an inert solvent in thepresence of from a catalytic amount to equivalent amount of a base.

The reaction temperature usually ranges from −20° C. to 100° C.,preferably at room temperature.

The reaction time usually ranges from 0.5 hour to 1 day.

Examples of the electron attractive group include carbonyl groups (suchas acyl, ester, carboxylic acid, and amide), cyano group, nitro group,sulfinyl group and sulfonyl group. Examples of the inert solvent whichcan be used in the above-described reaction include alcohol solvents,ether solvents, halogen solvents, aromatic solvents, nitrile solvents,amide solvents, ketone solvents, sulfoxide solvents and water. Two ormore of these solvents may be used as a mixture. Of these, methanol,methylene chloride, and tetrahydrofuran and so on are preferred.

(2) When R² Represents an Alkoxy Group or a Sulfide Group:

The compound (1) can be prepared by treating the compound (4), which isknown or can be prepared in a known manner, in the presence of an acidcatalyst, more specifically, by reacting the compound (4) with a thiolin the presence of an acid.

Described specifically, the compound (4) is reacted with from anequivalent to excess amount of a thiol in an inert solvent in thepresence of from a catalytic amount to equivalent amount of an acidcatalyst.

The reaction temperature usually ranges from −20° C. to 100° C.,preferably at room temperature.

The reaction time usually ranges from 0.5 hour to 1 day.

Examples of the acid which can be used in the above reaction includewater-free acid such as para-toluenesulfonic acid, camphor-sulfonicacid, hydrogen chloride and acid ion exchange resin; and Lewis acidcatalysts such as trimethylsilyl trifluoromethanesulfonate and borontrifluoride.

Examples of the inert solvent which can be used in the above reactioninclude ether solvents, halogen solvents, aromatic solvents, nitrilesolvents, and amide solvents. Two or more of the solvents may be used asa mixture. Of these, methylene chloride is preferred.Preparation Process of the Sulfide Compound (1: X═S) and the SulfonylCompound (1: X═SO₂): Reaction Scheme 5

1) Preparation Process of the Sulfide Compound (1: X═S)

The compound (1) can be prepared by subjecting an imine to thenucleophilic substitution reaction, more specifically, reacting an imineor iminium salt, which is the compound (5), with from an equivalent toan excess amount of a thiol in the presence of from a catalytic amountto excess amount of a base or an acid. The compound (5) can be preparedby mixing a carbonyl compound (R²COR³) with a primary or secondary amineor amide in a proper solvent.

The reaction temperature usually ranges from 0 to 100° C., preferably atroom temperature.

The reaction time usually ranges from 0.5 hour to 1 day.

Examples of the base which can be used in the above reaction includehydrides of an alkali metal or alkaline earth metal (such as lithiumhydride, sodium hydride, potassium hydride and calcium hydride); amidesof an alkali metal or alkaline earth metal (such as lithium amide,sodium amide, lithium diisopropylamide, lithium dicyclohexylamide,lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassiumhexamethyldisilazide); lower alkoxides of an alkali metal or alkalineearth metal (such as sodium methoxide, sodium ethoxide, and potassiumt-butoxide); hydroxides of an alkali metal, alkaline earth metal orsilver (such as silver hydroxide, sodium hydroxide, potassium hydroxide,lithium hydroxide and barium hydroxide); carbonates of an alkali metal,alkaline earth metal or silver (sodium carbonate, potassium carbonate,cesium carbonate and silver carbonate); bicarbonates of an alkali metal(such as sodium bicarbonate and potassium bicarbonate); alkyl lithiums(such as n-butyl lithium) or alkyl Grignard reagents (such as methylmagnesium bromide); inorganic bases such as silver oxide, or amines(such as triethylamine, diisopropylethylamine and N-methylmorpholine);and organic bases, for example, basic heterocyclic compounds (such asdimethylaminopyridine, pyridine, imidazole, 2,6-lutidine, collidine,1,8-diazabicyclo[5.4.0]undece-7-en, 1,5-diazabicyclo[4.3.0]non-5-en, and1,4-diazabicyclo[2.2.2]octane).

Examples of the acid which can be used in the above reaction includeformic acid, acetic acid, benzoic acid, para-toluenesulfonic acid andhydrochloric acid.

Examples of the inert solvent which can be used in the above reactioninclude alcohol solvents, ether solvents, nitrile solvents, amidesolvents, ketone solvents, sulfoxide solvents and water. Two or more ofthe solvents may be used as a mixture. Of these, a mixed solvent ofwater and tetrahydrofuran is preferred.

2) Preparation Process of the Sulfonyl Compound (1: X═SO₂)

The compound (1) can be prepared by subjecting an imine to thenucleophilic substitution reaction, more specifically, by reacting theimine or iminium salt, which is the compound (5), with from anequivalent amount to an excess amount of a sulfinic acid in the presenceof from a catalytic amount to excess amount of an acid.

The reaction temperature usually ranges from 0 to 100° C., preferably atroom temperature.

The reaction time usually ranges from 0.5 hour to 1 day.

Examples of the acid which can be used in the above reaction includeformic acid, acetic acid, benzoic acid, para-toluenesulfonic acid andhydrochloric acid.

The compound (5) can be prepared by mixing a carbonyl compound (R²COR³)with a primary or secondary amine or amide in a proper solvent.

The compound (1) is also available without isolation of the compound(5). For example, it is available only by reacting an aldehyde with anequivalent amount of amide or sulfinic acid in the presence of an excessamount of an acid in an inert solvent.

The reaction time usually ranges from 0 to 100° C., preferably at roomtemperature.

The reaction time ranges from 1 hour to 1 day.

Examples of the inert solvent which can be used in the above reactioninclude alcohol solvents, ether solvents, nitrile solvents, amidesolvents, ketone solvents, sulfoxide solvents and water. Two or more ofthese solvents may be used as a mixture. Of these, a mixed solvent ofwater and tetrahydrofuran is preferred.

The compounds (1) of the present invention, particularly the compoundsof the formula (3) strongly inhibit production or secretion of β-amyloidprotein so that they are useful as a medicament for prevention ortreatment for diseases resulting from abnormal production or secretionof β-amyloid protein, such as Alzheimer disease and Down syndrome ordiseases associated with amyloid deposition.

When the compound of the present invention is used as a pharmaceuticalfor human, the dose ranges from 1 mg to 1 g daily for adult, preferablyfrom 10 mg to 300 mg. When it is administered to animals, the dosevaries, depending on the purpose of administration (treatment orprevention), kind or size of the animal to be treated, the kind ordegree of bacteria with which the animal has been infected, but dailydose usually ranges from 0.1 mg to 200 mg, preferably from 0.5 mg to 100mg per kg of the weight of the animal. The daily dose is administeredonce a day or from two to four portions a day. The daily dose may exceedthe above-described amount, if necessary.

The pharmaceutical composition containing the compound of the presentinvention can be formulated into a desired form selected in accordancewith the administration route by using various ordinarily employedpreparation processes. Examples of the form of the pharmaceuticalcomposition having the invention compound as a main ingredient includeoral administrable preparations such as tablets, powders, granules,capsules, liquids, syrups, elixirs, oily or aqueous suspensions.

Injections may contain therein a stabilizer, antiseptic, solubilizingagent or the like. It is also possible to reconstitute a solidpreparation, which has been obtained by filling a vessel with a solutionwhich may contain such an agent and then lyophilizing it, upon use. Anamount to be administered once may be filled in one vessel or an amountto be administered plural times may be filled in one container.

Examples of the preparation for external use include liquids,suspensions, emulsions, ointments, gels, creams, lotions, sprays andplasters.

The solid preparation contains, together with the invention compound,pharmaceutically acceptable additives. It can be prepared by mixing theinvention compound with additives selected from fillers, extenders,binders, disintegrants, solubilizing promoters, humetants and lubricantsas needed.

Examples of the liquid preparations include solutions, suspensions andemulsions. They may contain a suspending agent or emulsifier as anadditive.

EXAMPLES

The present invention will be described hereinafter in detail withreference to embodiments of the present invention, but should not beconstrued as limited to the embodiments set forth herein. Also, all thecompounds exemplified hereinafter should be construed as belongingeither to E type or Z type unless specifically indicated.

Referential Example 1 1-(2,5-Difluorophenyl)-1-pentanol

At −78° C. under an argon atmosphere, n-butyl lithium (a 1.52M hexanesolution, 14.5 ml, 22.0 mmol) was added dropwise to a solution of1,4-difluorobenzaldehyde (2.84 g, 20.0 mmol) in tetrahydrofuran (40 ml).While stirring, the temperature of the reaction mixture was raised to−20° C. over 2 hours. To the reaction mixture was added a saturatedaqueous ammonium chloride solution, followed by extraction with ethylacetate. The extracts were combined, washed successively with water andbrine, dried over MgSO₄, and then concentrated. The residue thusobtained was purified by chromatography on a silica gel column (9% ethylacetate-hexane), whereby the title compound (2.62 g, 66%) was obtainedas a pale yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.90 (3H, t, J=7.3 Hz), 1.28-1.50 (4H, m),1.70-1.82 (2H, m), 1.91-1.95 (1H, br m), 4.98 (1H, dd, J=11.7, 5.9 Hz),6.88-7.00 (2H, m), 7.18 (1H, ddd, J=8.8, 5.6, 3.2 Hz).

Example 1 2-[1-[(4-Chlorophenyl)thio]pentyl]-1,4-difluorobenzene

At 0° C., 4-chlorobenzenethiol (435 mg, 3.00 mmol), triphenylphosphine(798 mg, 3.00 mmol), and diisopropyl azodicarboxylate (588 μl, 3.00mmol) were successively added to a solution of1-(2,5-difluorophenyl)-1-pentanol (300 mg, 1.50 mmol) in methylenechloride (6 ml). The reaction mixture was stirred at room temperaturefor 15 hours, diluted with methylene chloride, and then washedsuccessively with a 1N aqueous solution of sodium hydroxide and brine.After drying over MgSO₄, the mixture was concentrated. The residue thusobtained was purified twice by medium-pressure chromatography on asilica gel column (first time with 1% ethyl acetate-hexane, and secondtime with hexane), whereby the title compound (266 mg, 54%) was obtainedas a colorless oil.

IR (ATR) ν: 2958, 2931, 1624, 1595, 1574, 1493, 1475, 1425, 1389, 1234,1215, 1171, 1095, 1012, 874, 814 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.86 (3H, t, J=7.3 Hz), 1.22-1.41 (4H, m),1.78-1.88 (1H, m), 1.89-1.99 (1H, m), 4.48 (1H, ddd, J=8.6, 6.6, 1.7Hz), 6.81-6.86 (1H, m), 6.90 (1H, td, J=9.0, 4.6 Hz), 7.06 (1H, ddd,J=9.0, 5.8, 3.2 Hz), 7.17 (4H, s).

MS (m/z): 326 (M⁺).

HRMS (EI): as C₁₇H₁₇ClF₂S (M⁺)

Calculated: 326.0708

Found: 326.0696

Example 2 2-[1-[(4-Chlorophenyl)sulfinyl]pentyl]-1,4-difluorobenzene(Isomer 2-A and Isomer 2-B)

After addition of 3-chloroperbenzoic acid (301 mg, 1.74 mmol) to asolution of 2-[1-[(4-chlorophenyl)thio]pentyl]-1,4-difluorobenzene (515mg, 1.58 mmol) in methylene chloride (10 ml) at 0° C., the mixture wasstirred for 18 hours at room temperature. After further addition of3-chloroperbenzoic acid (100 mg, 0.578 mmol), the mixture was stirredfor 3 hours at room temperature. The reaction mixture was diluted withmethylene chloride, washed successively with a 1N aqueous solution ofsodium hydroxide, water, and brine, dried over MgSO₄, and concentrated.The residue thus obtained was purified by medium-pressure chromatographyon a silica gel column (10% ethyl acetate-hexane), whereby the titleIsomer 2-A (low-polarity) and the title Isomer 2-B (high-polarity) (230mg, 43%) were obtained each as a colorless oil. The resulting titleIsomer 2-A was then recrystallized from hexane and obtained as colorlessneedle crystals (79.8 mg, 15%).

Isomer 2-A

Melting point: 108.5-109.0° C.

IR (ATR) ν: 2929, 2854, 1493, 1275, 1132, 1174, 1086, 1043, 1011, 962,862, 823, 735, 503 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.90 (3H, t, J=7.1 Hz), 1.30-1.50 (4H, m),1.96-2.06 (1H, m), 2.27-2.36 (1H, m), 4.03 (1H, ddd, J=9.6, 6.1, 1.2Hz), 6.71 (1H, td, J=9.1, 4.4 Hz), 6.85-6.92 (1H, m), 7.07-7.12 (1H, m),7.10 (2H, d, J=8.6 Hz), 7.28 (2H, d, J=8.6 Hz).

MS (m/z) 343 (M⁺+H).

Elemental Analysis for C₁₇H₁₇ClF₂OS

Calculated: C, 59.56%; H, 5.00%; Cl, 10.34%; F, 11.08%; S, 9.35%.

Found: C, 59.27%; H, 4.91%; Cl, 10.42%; F, 11.05%; S, 9.45%.

Isomer 2-B

IR (ATR) ν: 3078, 2958, 2931, 2862, 1574, 1495, 1425, 1390, 1213, 1090,1051, 1012, 818, 741 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.83 (3H, t, J=7.1 Hz), 1.17-1.40 (4H, m),1.94-2.05 (1H, m), 2.24-2.34 (1H, m), 4.03 (1H, dd, J=12.0, 3.2 Hz),6.87-6.99 (3H, m), 7.26 (2H, d, J=8.3 Hz), 7.35 (2H, d, J=8.3 Hz).

MS (m/z): 343 (M⁺+H).

HRMS (FAB) for C₁₇H₁₈OClF₂S (M⁺+H)

Calculated: 343.0735

Found: 343.0750

Example 3 2-[1-[(4-Chlorophenyl)sulfonyl]pentyl]-1,4-difluorobenzene

After addition of 3-chloroperbenzoic acid (98.8 mg, 0.571 mmol) to asolution of 2-[1-[(4-chlorophenyl)sulfinyl]pentyl]-1,4-difluorobenzene(Isomer 2-B) (150 mg, 0.439 mmol) in methylene chloride (5 ml), theresulting mixture was stirred at room temperature for 18 hours. Thereaction mixture was diluted with methylene chloride, washedsuccessively with a 1N aqueous solution of sodium hydroxide, water andbrine, dried over MgSO₄, and concentrated. The residue thus obtained waspurified by medium-pressure chromatography on a silica gel column (10%ethyl acetate-hexane), whereby the title compound (122 mg, 77%) wasobtained as a colorless oil.

IR (ATR) ν: 3089, 2958, 2933, 2873, 1583, 1496, 1475, 1427, 1394, 1321,1279, 1219, 1176, 1149, 1086, 1014, 829, 754 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.85 (3H, t, J=7.3 Hz), 1.15-1.40 (4H, m),2.03-2.14 (1H, m), 2.38-2.47 (1H, m), 4.51 (1H, dd, J=10.5, 3.7 Hz),6.83 (1H, td, J=9.0, 4.6 Hz), 6.94-7.01 (1H, m), 7.25 (1H, ddd, J=8.8,5.4, 3.2 Hz), 7.38 (2H, d, J=8.5 Hz), 7.53 (2H, d, J=8.5 Hz).

MS (m/z): 359 (M⁺+H).

HRMS (FAB) for C₁₇H₁₈ClF₂O₂S (M⁺+H)

Calculated: 359.0684

Found: 359.0688

Example 4 2-[(4-Chlorophenyl)thiomethyl]-1,4-difluorobenzene

Process 1: At 0° C., 4-chlorobenzenethiol (5.45 g, 38.2 mmol),triphenylphosphine (11.1 g, 41.6 mmol), and diisopropyl azodicarboxylate(8.16 ml, 41.6 mmol) were added successively to a solution of2,5-difluorobenzyl alcohol (5.00 g, 34.7 mmol) in tetrahydrofuran (150ml). The reaction mixture was stirred at room temperature for 4 days,followed by concentration. The residue thus obtained was purified bychromatography on a silica gel column (1% ethyl acetate-hexane), wherebythe title compound (2.68 g, 29%) was obtained as a colorless oil.

Process 2: After addition of potassium carbonate (4.00 g, 29.0 mmol) and2-bromomethyl-1,4-difluorobenzene (5.00 g, 24.2 mmol) to a solution of4-chlorobenzenethiol (3.86 g, 26.6 mmol) in N,N-dimethylformamide (120ml), the mixture was stirred for 3 hours at room temperature. To thereaction mixture were added saturated ammonium chloride (50 ml) andwater (20 ml), followed by extraction with diethyl ether. The extractswere combined, washed with water and brine, dried over MgSO₄, andconcentrated. The residue thus obtained was purified by chromatographyon a silica gel column (1% ethyl acetate-hexane), whereby the titlecompound (6.41 g, 98%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 4.04 (2H, s), 6.85-7.00 (3H, m), 7.23 (4H,s).

Example 5 2-[(4-Chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene

Process 1: At 0° C., 3-chloroperbenzoic acid (225 mg, 1.30 mmol) wasadded to a solution of2-[(4-chlorophenyl)thiomethyl]-1,4-difluorobenzene (271 mg, 1.00 mmol)in methylene chloride (5 ml). The mixture was then stirred at roomtemperature for 15 hours. The reaction mixture was diluted withmethylene chloride, washed with a saturated aqueous solution ofpotassium bicarbonate and brine, dried over MgSO₄, and concentrated. Theresidue thus obtained was dissolved in methylene chloride (5 ml). Aftercooling to 0° C., 3-chloroperbenzoic acid (450 mg, 2.60 mmol) was addedto the solution and then the mixture was stirred at room temperature for15 hours. The reaction mixture was diluted with methylene chloride,washed with a saturated aqueous solution of potassium bicarbonate andbrine, dried over MgSO₄, then concentrated. The residue thus obtainedwas purified by chromatography on a silica gel column (9% ethylacetate-hexane), whereby the title compound (210 mg, 69%) was obtainedas a colorless solid.

Process 2: After addition of H₂O (16.4 ml), 30% H₂O₂ (16.4 ml, 145 mmol)and hexaammonium heptamolybdate tetrahydrate (425 mg, 0.344 mmol) to asolution of 2-[(4-chlorophenyl)thiomethyl]-1,4-difluorobenzene (6.54 g,24.1 mmol) in methanol (100 ml) at 0° C., the mixture was stirred for 1hour and then stirred further for 15 hours at room temperature. Thesolid thus precipitated was collected by filtration and the filtrate wasconcentrated to about half of its amount. The resulting aqueous solutionwas extracted with methylene chloride. The solid was then dissolved inthe extract. The resulting solution was washed successively with waterand brine, dried over MgSO₄, and concentrated. The residue thus obtainedwas recrystallized from hexane, whereby the title compound (6.34 g, 87%)was obtained as colorless needle crystals.

Process 3: After addition of 2-bromomethyl-1,4-difluorobenzene (12.3 ml,95.5 mmol) to a suspension of sodium 4-chlorobenzenesulfinate (19.0 g,95.5 mmol) in butanol (200 ml), the mixture was heated under reflux for5 hours. The solid thus precipitated was collected by filtration anddissolved in methylene chloride. The resulting solution was washed withbrine, dried over MgSO₄, and concentrated. The solid thus obtained wasrecrystallized from hexane, whereby the title compound (12.3 g, 43%) wasobtained as colorless needle crystals. The filtrate was extracted withmethylene chloride. The extract was washed with water and brine, driedover MgSO₄, and concentrated. The solid thus obtained was washed withhexane, and dissolved in diethyl ether. After removal of an insolublematter, the residue was concentrated. The solid was recrystallized fromhexane, whereby the title compound (12.7 g, 44%) was obtained.

IR (ATR) ν: 3089, 2991, 2943, 1581, 1496, 1315, 1279, 1213, 1149, 1090,1080, 1012, 958, 816, 779, 756, 729, 708, 646, 517, 469 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 4.36 (2H, s), 6.91 (1H, td, J=9.0, 4.4 Hz),6.99-7.06 (1H, m), 7.11 (1H, ddd, J=8.3, 5.6, 3.2 Hz), 7.45 (2H, d,J=8.8 Hz), 7.62 (2H, d, J=8.8 Hz).

MS (m/z): 303 (M⁺+H).

Example 6E-2-[1-[(4-Chlorophenyl)sulfonyl]-2-phenylethenyl]-1,4-difluorobenzene

Under a nitrogen atmosphere and at 0° C., potassium hexamethyldisilazide(a 0.5M toluene solution, 2.20 ml, 1.10 mmol) was added to atetrahydrofuran (5 ml) solution of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (303 mg, 1.00mmol) obtained in Example 5 was added. The resulting mixture was stirredat 0° C. for 1 hour. After addition of benzaldehyde (127 mg, 1.20 mmol),the mixture was stirred at room temperature for 15 hours. The reactionmixture was added with a saturated aqueous solution of ammoniumchloride, followed by extraction with ethyl acetate. The extracts werecombined, washed successively with water and brine, dried over MgSO₄,and concentrated. The residue thus obtained was purified bymedium-pressure chromatography on a silica gel column (10% ethylacetate-hexane), whereby the title compound (220 mg, 56%) was obtainedas a colorless solid. The solid was recrystallized from methanol toyield a colorless solid (111 mg, 28%). Based on the observation test ofNOE (Nuclear Overhauser Effect), the olefin of the title compound wasdetermined as an E-form.

Melting point: 144.5-145.0° C.

IR (KBr) ν: 3068, 1637, 1581, 1489, 1450, 1419, 1315, 1246, 1155, 1086,887, 814, 752, 725, 690, 648, 627, 613, 534, 467 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 6.88 (1H, td, J=9.1, 4.4 Hz), 7.06-7.18 (4H,m), 7.22-7.28 (2H, m), 7.30-7.36 (1H, m), 7.39 (2H, d, J=8.8 Hz), 7.60(2H, d, J=8.8 Hz), 8.09 (1H, s).

MS (m/z): 391 (M⁺+H).

Elemental Analysis for C₂₀H₁₃ClF₂O₂S

Calculated: C, 61.46%; H, 3.35%; Cl, 9.07%; F, 9.72%; S, 8.20%.

Found: C, 61.39%; H, 3.28%; Cl, 8.95%; F, 9.82%; S, 8.30%.

Example 71-[(4-Chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-pentanone

In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexanesolution, 1.27 ml, 2.00 mmol) was added to a tetrahydrofuran (10 ml)solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene(606 mg, 2.00 mmol) obtained in Example 5. The temperature of theresulting mixture was then raised to room temperature. After cooling to−78° C., butyryl chloride (0.218 ml, 2.10 mmol) was added dropwise tothe reaction mixture. The reaction mixture was stirred at −78° C. for1.5 hours, and added with 1N hydrochloric acid (2.0 ml). The temperatureof the mixture was then raised to room temperature. The reaction mixturewas extracted with diethyl ether. The extracts were combined, washedsuccessively with water and brine, dried over MgSO₄, and concentrated.The residue thus obtained was purified by medium-pressure chromatographyon a silica gel column (10% ethyl acetate-hexane). The solid thusobtained was recrystallized from hexane, whereby the title compound (330mg, 44%) was obtained as colorless needle crystals.

Melting point: 85.5-86.0° C.

IR (ATR) ν: 2968, 1724, 1581, 1491, 1394, 1335, 1323, 1155, 1088, 1034,1011, 906, 829, 816, 758, 725, 615, 546, 469 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.90 (3H, t, J=7.6 Hz), 1.52-1.68 (2H, m),2.62 (1H, ddd, J=18.1, 7.6, 6.8 Hz), 2.84 (1H, ddd, J=18.1, 7.6, 6.8Hz), 5.66 (1H, s), 6.95 (1H, td, J=9.0, 4.4 Hz), 7.02-7.08 (1H, m),7.39-7.43 (1H, m), 7.43 (2H, d, J=8.5 Hz), 7.56 (2H, d, J=8.5 Hz).

MS (m/z) 372 (M⁺).

Elemental Analysis for C₁₇H₁₅ClF₂O₃S

Calculated: C, 54.77%; H, 4.06%; Cl, 9.51%; F, 10.19%; S, 8.60%.

Found: C, 54.47%; H, 3.92%; Cl, 9.68%; F, 10.26%; S, 8.76%.

Example 82-[(4-Chlorophenyl)sulfonyl]-2-(2,5-difluorophenyl)-1-phenyl-1-ethanone

In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexanesolution, 0.701 ml, 1.10 mmol) was added to a tetrahydrofuran (5 ml)solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene(303 mg, 1.00 mmol) obtained in Example 5. The temperature of theresulting mixture was raised to room temperature and then stirred for 10minutes. After cooling the reaction mixture to −78° C., benzoyl chloride(0.140 ml, 1.20 mmol) was added thereto dropwise. The reaction mixturewas stirred at −78° C. for 30 minutes. The temperature of the mixturewas then raised to O° C. over 3 hours. After addition of 1N hydrochloricacid (2.0 ml), the mixture was extracted with ethyl acetate. Theextracts were combined, washed successively with water, a saturatedaqueous solution of sodium bicarbonate, and brine, dried over MgSO₄, andthen concentrated. The residue was purified by medium-pressurechromatography on a silica gel column (10% ethyl acetate-hexane). Thesolid thus obtained was washed with hexane, whereby the title compound(200 mg, 49%) was obtained as a colorless solid.

Melting point: 179.5-180.0° C.

IR (ATR) ν: 1682, 1595, 1579, 1495, 1475, 1315, 1284, 1240, 1209, 1153,1082, 991, 874, 766, 708, 687, 607, 547, 509, 453 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 6.54 (1H, s), 7.01-7.10 (2H, m), 7.34-7.38(1H, m), 7.44-7.50 (4H, m), 7.58-7.65 (1H, m), 7.67 (2H, d, J=8.8 Hz),7.88-7.93 (2H, m)

MS (m/z): 406 (M⁺).

HRMS (EI): as C₂₀H₁₃ClF₂O₃S (M⁺)

Calculated: 406.0242

Found: 406.0230

Example 92-[(4-Chlorophenyl)sulfonyl]-2-(2,5-difluorophenyl)-1-phenylethenylbenzoate

In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexanesolution, 0.701 ml, 1.10 mmol) was added to a dimethoxyethane (5 ml)solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene(303 mg, 1.00 mmol) obtained in Example 5. The temperature of themixture was then raised to room temperature, followed by stirring for 10minutes. After cooling to −78° C., benzoyl chloride (0.140 ml, 1.20mmol) was added dropwise to the reaction mixture. The reaction mixturewas stirred at −78° C. for 30 minutes. The temperature of the mixturewas then raised to 0° C. over 3 hours. A saturated aqueous ammoniumchloride solution was added to the reaction mixture, followed byextraction with diethyl ether. The extracts were combined, washedsuccessively with water and brine, dried over MgSO₄, and thenconcentrated. The residue was purified by medium-pressure chromatographyon a silica gel column (10% ethyl acetate-hexane). The solid thusobtained was recrystallized from ethyl acetate, whereby the titlecompound (80.0 mg, 26%) was obtained as a colorless solid.

Melting point: 224.5-227.0° C.

IR (ATR) ν: 1756, 1610, 1491, 1450, 1325, 1228, 1155, 1092, 1072, 1011,808, 756, 694, 606, 553, 462 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 6.97 (1H, ddd, J=8.8, 4.4 Hz), 7.02-7.09 (1H,m), 7.15-7.21 (3H, m), 7.23-7.30 (3H, m), 7.34 (2H, d, J=8.5 Hz),7.51-7.57 (2H, m), 7.77 (2H, d, J=8.5 Hz), 8.02-8.06 (2H, m).

MS (m/z): 528 (M⁺+NH₄).

Elemental Analysis for C₂—H₁₇ClF₂O₄S

Calculated: C, 63.47%; H, 3.35%; Cl, 6.94%; F, 7.44%; S, 6.28%.

Analyzed: C, 63.04%; H, 3.24%; Cl, 6.92%; F, 7.39%; S, 6.44%.

Example 101-[(4-Chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-pentanol

Under a nitrogen atmosphere and at −78° C., n-butyl lithium (a 1.60Mhexane solution, 0.688 ml, 1.10 mmol) was added to a tetrahydrofuran (5ml) solution of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (303 mg, 1.00mmol) obtained in Example 5. The mixture was stirred at −78° C. for 1hour. After addition of butanal (0.108 ml, 1.20 mmol), the mixture wasstirred at −78° C. for 2 hours. A saturated aqueous ammonium chloridesolution was added to the reaction mixture, followed by extraction withethyl acetate. The extracts were combined, washed successively withwater and brine, dried over MgSO₄, and then concentrated. The residuewas purified by medium-pressure chromatography on a silica gel column(10% ethyl acetate-hexane) as a low-polarity isomer to yield by acolorless solid. The solid thus obtained was washed with hexane, wherebythe title compound (30.5 mg, 8%) was obtained as a colorless solid.

Melting point: 134.5-135.0° C.

IR (ATR) ν: 3502, 2966, 2931, 2873, 1585, 1491, 1309, 1277, 1227, 1173,1147, 1084, 1083, 1014, 810, 756, 721, 613, 542, 445 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.87 (3H, t, J=7.1 Hz), 1.20-1.65 (4H, m),3.06 (1H, d, J=2.2 Hz), 4.48 (1H, s), 4.85-4.90 (1H, m), 6.84 (1H, td,J=9.1, 4.7 Hz), 6.96-7.02 (1H, m), 7.40 (2H, d, J=8.6 Hz), 7.58 (2H, d,J=8.6 Hz), 7.85 (1H, ddd, J=9.1, 5.4, 3.4 Hz).

MS (m/z): 374 (M⁺).

HRMS (EI) m/z as C₁₇H₁₇O₃ClF₂S (M⁺):

Calculated: 374.0555

Found: 374.0540

Example 111-[(4-Chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-pentanol

In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexanesolution, 7.01 ml, 11.0 mmol) was added to a tetrahydrofuran (50 ml)solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene(3.03 g, 10.0 mmol) obtained in Example 5 and the mixture was stirred at−78° C. for 1 hour. Butanal (1.08 ml, 12.0 mmol) was added dropwise tothe reaction mixture. The mixture was stirred for 15 hours whileelevating its temperature to room temperature. After cooling to 0° C.and addition of a saturated aqueous ammonium chloride solution, themixture was extracted with diethyl ether. The extracts were combined,washed successively with water and brine, dried over MgSO₄, and thenconcentrated. The solid thus precipitated was collected by filtrationand washed with hexane. The filtrate and washing with hexane werecombined, followed by concentration. The residue was purified bymedium-pressure chromatography on a silica gel column (10% ethylacetate-hexane) as a high-polarity isomer to yield a colorless solid.The resulting colorless solid was recrystallized from hexane, wherebythe title compound (396 mg, 11%) was obtained as colorless needlecrystals.

Melting point: 76.5-78.0° C.

IR (ATR) ν: 3533, 2960, 1581, 1498, 1394, 1329, 1306, 1242, 1178, 1146,1082, 987, 887, 754, 712, 644, 594, 515 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.82 (3H, t, J=7.3 Hz), 1.22-1.53 (4H, m),3.78 (1H, br s), 4.55-4.80 (2H, br m), 6.84 (1H, td, J=9.0, 4.4 Hz),6.96-7.04 (1H, m), 7.15-7.26 (1H, br s), 7.39 (2H, d, J=8.3 Hz), 7.52(2H, d, J=8.3 Hz).

MS (m/z): 374 (M⁺).

Elemental Analysis for C₁₇H₁₇ClF₂O₃S

Calculated: C, 54.47%; H, 4.57%; Cl, 9.46%; F, 10.14%; S, 8.55%.

Found: C, 54.27%; H, 4.51%; Cl, 9.44%; F, 10.20%; S, 8.70%.

Example 122-[1-[(4-Chlorophenyl)sulfonyl]-1-penten-1-yl]-1,4-difluorobenzene

At 0° C., triethylamine (0.131 ml, 0.942 mmol) and methanesulfonylchloride (0.0665 ml, 0.856 mmol) were added to a solution of1-[(4-chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-pentanol (204 mg,0.544 mmol) in methylene chloride (10 ml). After stirring at 0° C. for 1hour, the reaction mixture was diluted with methylene chloride, washedsuccessively with a saturated aqueous ammonium chloride solution, waterand brine, dried over MgSO₄, and then concentrated. The residue wasdissolved in tetrahydrofuran (5 ml). After cooling the solution to 0°C., potassium hexamethyldisilazide (a 0.5M toluene solution, 1.30 ml,0.650 mmol) was added thereto. The resulting mixture was stirred at 0°C. for 3 hours, and saturated ammonium chloride was added thereto. Theresulting mixture was extracted with ethyl acetate, washed successivelywith water and brine, dried over MgSO₄, and then concentrated. Theresidue thus obtained was purified by medium-pressure chromatography ona silica gel column (15% ethyl acetate-hexane). The resulting solid wasrecrystallized from hexane, whereby the title compound (33.0 mg, 17%)was obtained as colorless needle crystals.

Melting point: 95.5-97.0° C.

IR (ATR) ν: 2960, 1645, 1579, 1489, 1421, 1311, 1252, 1198, 1165, 1140,1086, 1012, 818, 769, 752, 640, 606, 552, 467 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.89 (3H, t, J=7.3 Hz), 1.45-1.56 (2H, m),2.00 (2H, br s), 6.89 (1H, td, J=8.3, 4.4 Hz), 7.01-7.08 (2H, m), 7.31(1H, t, J=8.3 Hz), 7.38 (2H, d, J=8.5 Hz), 7.55 (2H, d, J=8.5 Hz).

MS (m/z): 356 (M⁺).

HRMS (EI): as C₁₇H₁₅ClF₂O₂S (M⁺)

Calculated: 356.0449

Found: 356.0450

Elemental Analysis for C₁₇H₁₅ClF₂O₂S

Calculated: C, 57.22%; H, 4.24%; Cl, 9.94%; F, 10.65%; S, 8.99%.

Found: C, 56.80%; H, 4.21%; Cl, 10.04%; F, 10.65%; S, 9.11%.

Example 13 1-[(4-Chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-pentylmethanesulfonate

At 0° C., triethylamine (0.300 ml, 2.16 mmol) and methanesulfonylchloride (0.150 ml, 1.93 mmol) were added to a methylene chloride (10ml) solution of the1-[(4-chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-pentanol (449 mg,1.20 mmol) obtained in Example 11. The resulting mixture was thenstirred at 0° C. for 2 hours. The reaction mixture was diluted withmethylene chloride, washed successively with a saturated aqueoussolution of ammonium chloride, water and brine, dried over MgSO₄, thenconcentrated. The residue thus obtained was purified by medium-pressurechromatography on a silica gel column (15% ethyl acetate-hexane),whereby the title compound (503 mg, 93%) was obtained as a colorlesssolid.

IR (ATR) ν: 2966, 1498, 1350, 1176, 1149, 1086, 928, 879, 789, 752, 636,592, 550, 525, 455 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.86 (3H, t, J=7.1 Hz), 1.33-1.61 (3H, m),1.88-1.96 (1H, m), 3.21 (3H, d, J=0.7 Hz), 5.03 (1H, d, J=7.7 Hz),5.58-5.66 (1H, m), 6.83 (1H, td, J=9.0, 4.4 Hz), 6.97-7.05 (1H, m),7.33-7.40 (1H, m, including 2H, d, J=8.3 Hz at 7.35 ppm), 7.54 (2H, d,J=8.3 Hz).

Example 142-[1-[(4-Chlorophenyl)sulfonyl]-2-penten-1-yl]-1,4-difluorobenzene

To a solution of1-[(4-chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-pentyl=methanesulfonato(200 mg, 0.442 mmol) in methylene chloride (4 ml) was added1,8-diazabicyclo[5,4,0]undec-7-ene (69.1 μl, 0.464 mmol) at roomtemperature. The mixture was stirred for 15 hours. The reaction mixturewas concentrated. The residue was purified by medium-pressurechromatography on a silica gel column (8% ethyl acetate-hexane), wherebythe title compound (72.0 mg, 46%) was obtained as a colorless solid. Theresulting solid was recrystallized from hexane to yield a colorlesssolid (60.0 mg).

Melting point: 99.0-100.0° C.

IR (ATR) ν: 1581, 1496, 1392, 1309, 1279, 1232, 1173, 1149, 1084, 978,837, 816, 806, 758, 731, 710, 644, 598, 561, 521 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.99 (3H, t, J=7.3 Hz), 2.12 (2H, m), 5.06(2H, d, J=7.3 Hz), 5.74-5.85 (2H, m), 6.92 (1H, td, J=9.0, 4.4 Hz),6.97-7.04 (1H, m), 7.32 (1H, ddd, J=8.5, 5.4, 3.2 Hz), 7.43 (2H, d,J=8.5 Hz), 7.64 (2H, d, J=8.5 Hz).

MS (m/z): 374 (M⁺+NH₄).

Elemental Analysis for C₁₇H₁₅ClF₂O₂S

Calculated: C, 57.22%; H, 4.24%; Cl, 9.94%; F, 10.65%; S, 8.99%.

Analyzed: C, 57.15%; H, 4.18%; Cl, 9.90%; F, 10.74%; S, 9.09%.

Example 152-[S-(t-Butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]pentyl]-1,4-difluorobenzene

In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexanesolution, 0.701 ml, 1.10 mmol) was added to a dimethoxyethane (5 ml)solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene(303 mg, 1.00 mmol) obtained in Example 5. The mixture was stirred at−78° C. for 1 hour and then, at room temperature for 30 minutes. Thereaction mixture was cooled to −78° C., followed by the dropwiseaddition of 4-(t-butyldimethylsilyloxy)-1-iodobutane (0.260 ml, 1.00mmol). While elevating the temperature of the reaction mixture to roomtemperature, stirring was conducted for 15 hours. Water was added to thereaction mixture, followed by extraction with diethyl ether. Theextracts were combined, washed successively with water and brine, driedover MgSO₄, and concentrated. The residue thus obtained was purified bymedium-pressure chromatography on a silica gel column (8% ethylacetate-hexane), whereby the title compound (401 mg, 82%) was obtainedas a colorless solid. The resulting solid was recrystallized from hexaneto yield colorless needle crystals.

IR (ATR) ν: 2945, 2927, 2854, 1583, 1496, 1427, 1392, 1321, 1248, 1144,1082, 1038, 1012, 941, 822, 775, 748, 708, 623, 542, 467 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: −0.02 (3H, s), −0.02 (3H, s), 0.82 (9H, s),1.23-1.33 (2H, m), 1.42-1.58 (2H, m), 2.06-2.18 (1H, m), 2.39-2.48 (1H,m), 3.53 (2H, t, J=6.3 Hz), 4.52 (1H, dd, J=11.6, 2.6 Hz), 6.83 (1H, td,J=9.0, 4.4 Hz), 6.94-7.00 (1H, m), 7.22-7.26 (1H, m), 7.38 (2H, d, J=8.5Hz), 7.53 (2H, d, J=8.5 Hz).

MS (m/z): 489 (M⁺+H).

Elemental Analysis for C₂₃H₃₁ClF₂O₃SSi

Calculated: C, 56.48%; H, 6.39%; Cl, 7.25%; F, 7.77%; S, 6.56%.

Analyzed: C, 56.29%; H, 6.28%; Cl, 7.29%; F, 7.75%; S, 6.70%.

Example 162-[5-(t-Butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-1-methylpentyl]-1,4-difluorobenzene

In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexanesolution, 0.294 ml, 0.461 mmol) was added to a solution of2-[5-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]pentyl]-1,4-difluorobenzene(205 mg, 0.419 mmol) in tetrahydrofuran (4 ml). The mixture was stirredat room temperature for 1 hour. After cooling to −78° C., iodomethane(0.339 ml, 0.545 mmol) was added dropwise to the reaction mixture andthe mixture was stirred at room temperature for 4 hours. Water was addedto the reaction mixture, followed by extraction with diethyl ether. Theextracts were combined, washed successively with water and brine, driedover MgSO₄, and then concentrated. The residue thus obtained waspurified by medium-pressure chromatography on a silica gel column (6%ethyl acetate-hexane), whereby the title compound (168 mg, 80%) wasobtained as a colorless oil.

IR (ATR) ν: 2952, 2929, 2856, 1583, 1496, 1473, 1392, 1311, 1255, 1192,1149, 1090, 1014, 833, 760, 710, 629, 552 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: −0.01 (3H, s), 0.00 (3H, s), 0.84 (9H, s),1.05-1.18 (1H, m), 1.29-1.41 (1H, m), 1.52-1.60 (2H, m), 1.81 (3H, d,J=2.9 Hz), 1.95-2.05 (1H, m), 2.61-2.71 (1H, m), 3.57 (2H, t, J=6.1 Hz),6.82-6.88 (1H, m), 6.98-7.07 (2H, m), 7.38 (2H, d, J=9.1 Hz), 7.40 (2H,d, J=9.1 Hz).

MS (m/z): 503 (M⁺).

HRMS (FAB) for C₂₄H₃₄ClF₂O₃SSi (M⁺+H)

Calculated: 503.1655

Analyzed: 503.1704

Example 17 5-(4-Chlorophenylsulfonyl)-5-(2,5-difluorophenyl)-1-hexanol

After addition of tetrabutylammonium fluoride (a 1M tetrahydrofuransolution, 0.978 ml, 0.978 mmol) to a solution of2-[5-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-1-methylpentyl]-1,4-difluorobenzene(164 mg, 0.326 mmol) in tetrahydrofuran (4 ml), the mixture was stirredat room temperature for 3 hours. The reaction mixture was diluted withdiethyl ether, washed successively with saturated ammonium chloride,water and brine, dried over MgSO₄, and then concentrated. The residuethus obtained was purified by medium-pressure chromatography on a silicagel column (50% ethyl acetate-hexane), whereby the title compound (122mg, 96%) was obtained as a colorless oil.

IR (ATR) ν: 3516, 3089, 2939, 2870, 1583, 1495, 1475, 1412, 1394, 1306,1279, 1188, 1146, 1088, 1070, 1012, 823, 758, 710, 679, 649, 602, 546,474 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 2.09-2.20 (1H, m), 1.23 (1H, br s), 1.34-1.46(1H, m), 1.63 (1H, quint, J=7.1 Hz), 1.82 (3H, d, J=2.7 Hz), 1.98-2.07(1H, m), 2.71 (1H, td, J=13.0, 3.4 Hz), 3.63 (2H, t, J=6.4 Hz),6.83-6.90 (1H, m), 6.99-7.06 (2H, m), 7.38 (4H, s).

MS (m/z): 389 (M⁺+H)

HRMS (FAB) for C₁₈H₂₀ClF₂O₃S (M⁺+H)

Calculated: 389.0790

Analyzed: 389.0795

Example 182-[5-(t-Butyldimethylsilyloxy)-1-[4-(t-butyldimethylsilyloxy)butyl]-1-(4-chlorophenylsulfonyl)pentyl]-1,4-difluorobenzene

In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexanesolution, 0.358 ml, 0.562 mmol) was added to a tetrahydrofuran (4 ml)solution of the2-[5-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]pentyl]-1,4-difluorobenzene(250 mg, 0.511 mmol) obtained in Example 15. The temperature of theresulting mixture was raised to room temperature. After cooling to −78°C., 4-(t-butyldimethylsilyloxy)-1-iodobutane (0.146 ml, 0.562 mmol) wasadded dropwise to the reaction mixture. The reaction mixture was stirredat room temperature for 3 days. Water was added to the reaction mixture,followed by extraction with diethyl ether. The extracts were combined,washed successively with water and brine, dried over MgSO₄, and thenconcentrated. The residue thus obtained was purified by medium-pressurechromatography on a silica gel column (6% ethyl acetate-hexane), wherebythe title compound (167 mg, 48%) was obtained as a colorless solid.

IR (ATR) ν: 3082, 2927, 2856, 1583, 1495, 1462, 1308, 1250, 1146, 1080,1012, 833, 758, 675, 646, 607, 579, 544, 455 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.03 (12H, s), 0.87 (18H, s), 1.25-1.70 (8H,m), 2.23-2.34 (2H, m), 2.40-2.48 (2H, m), 3.58-3.68 (4H, m), 6.74-6.82(1H, m), 6.97-7.06 (2H, m), 7.30 (2H, d, J=8.8 Hz), 7.34 (2H, d, J=8.8Hz).

MS (m/z): 675 (M⁺+H).

HRMS (FAB) for C₃₃H₅₄ClF₂O₄SSi₂ (M⁺+H)

Calculated: 675.2938

Analyzed: 675.2900

Elemental Analysis for C₃₃H₅₃ClF₂O₄SSi₂

Calculated: C, 58.68%; H, 7.91%; Cl, 5.25%; F, 5.63%.

Analyzed: C, 58.63%; H, 7.91%; Cl, 5.32%; F, 5.69%.

Example 195-[(4-Chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-1,9-nonanediol

To a solution of2-[5-(t-butyldimethylsilyloxy)-1-[4-(t-butyldimethylsilyloxy)butyl]-1-(4-chlorophenylsulfonyl)pentyl]-1,4-difluorobenzene(158 mg, 0.234 mmol) in tetrahydrofuran (4 ml) was addedtetrabutylammonium fluoride (a 1M tetrahydrofuran solution, 0.702 ml,0.702 mmol). The resulting mixture was stirred at room temperature for24 hours. After concentration of the reaction mixture, the residue wasdissolved in diethyl ether, followed by successive washing with waterand brine, drying over MgSO₄, and concentration. The residue thusobtained was purified by medium-pressure chromatography on a silica gelcolumn (5% methanol-methylene chloride) to yield a colorless solid. Theresulting solid was recrystallized from ethyl acetate-hexane, wherebythe title compound (97.0 mg, 93%) was obtained as a colorless solid.

Melting point: 107.0-108.5° C.

IR (ATR) ν: 3275, 2939, 1572, 1495, 1414, 1306, 1261, 1140, 1078, 1066,847, 812, 754, 710, 679, 644, 606, 544, 474, 449 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.36-1.82 (10H, m), 2.24-2.35 (2H, m),2.47-2.57 (2H, m), 3.70 (4H, t, J=5.9 Hz), 6.79 (1H, ddd, J=12.4, 8.3,4.6 Hz), 6.97-7.08 (2H, m), 7.29 (2H, d, J=8.8 Hz), 7.34 (2H, d, J=8.8Hz).

MS (m/z): 447 (M⁺+H).

HRMS (FAB) for C₂₁H₂₆ClF₂O₄S (M⁺+H)

Calculated: 447.1208

Found: 447.1227

Elemental Analysis for C₂₁H₂₅ClF₂O₄S.0.25H₂O

Calculated: C, 55.87%; H, 5.69%; Cl, 7.85%; F, 8.42%; S, 7.10%.

Analyzed: C, 55.62%; H, 5.40%; Cl, 7.89%; F, 8.58%; S, 7.26%.

Example 202-[5-(t-Butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-1-butylpentyl]-1,4-difluorobenzene

In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexanesolution, 0.287 ml, 0.450 mmol) was added to a tetrahydrofuran (4 ml)solution of the2-[5-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]pentyl]-1,4-difluorobenzene(200 mg, 0.409 mmol) obtained in Example 15. The temperature of theresulting mixture was raised to room temperature. After cooling to −78°C., hexamethylphosphoric triamide (0.214 ml, 1.23 mmol) and iodobutane(51.1 μl, 0.450 mmol) were added dropwise to the reaction mixture. Theresulting mixture was stirred at room temperature for 20 hours.Isopropanol (0.5 ml) was added to the reaction mixture, followed byconcentration. The residue thus obtained was purified by medium-pressurechromatography on a silica gel column (5% ethyl acetate-hexane), wherebythe title compound (163 mg, 73%) was obtained as a colorless oil.

IR (ATR) ν: 2954, 2929, 2858, 1583, 1495, 1473, 1412, 1394, 1311, 1255,1192, 1147, 1090, 1014, 833, 756, 710, 677, 606 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.03 (6H, s), 0.87 (9H, s), 0.95 (3H, t,J=7.4 Hz), 1.20-1.45 (5H, m), 1.52-1.70 (3H, m), 2.21-2.32 (2H, m),2.40-2.49 (2H, m), 3.64 (2H, t, J=6.1 Hz), 6.74-6.82 (1H, m), 6.97-7.07(2H, m), 7.29 (2H, d, J=8.8 Hz), 7.34 (2H, d, J=8.8 Hz).

MS (m/z): 545 (M⁺).

HRMS (FAB) for C₂—H₄₀ClF₂O₃SSi (M⁺+H)

Calculated: 545.2124

Analyzed: 545.2087

Example 21 5-[(4-Chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-1-nonanol

After addition of tetrabutylammonium fluoride (a 1M tetrahydrofuransolution, 0.532 ml, 0.532 mmol) to a solution of2-[5-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-1-butylpentyl]-1,4-difluorobenzene(154 mg, 0.283 mmol) in tetrahydrofuran (4 ml), the mixture was stirredat room temperature for 18 hours. The reaction mixture was thenconcentrated. The residue thus obtained was dissolved in diethyl ether,followed by successive washing with water and brine, drying over MgSO₄,and concentration. The residue thus obtained was purified bymedium-pressure chromatography on a silica gel column (50% ethylacetate-hexane), whereby the title compound (122 mg, 0.283 mmol) wasobtained as a colorless oil.

IR (ATR) ν: 3539, 2958, 2873, 1583, 1495, 1412, 1308, 1277, 1192, 1146,1090, 1014, 829, 758, 710, 675, 606, 548, 463 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.95 (3H, t, J=7.3 Hz), 1.19-1.77 (9H, m),2.21-2.34 (2H, m), 2.38-2.53 (2H, m), 3.70 (2H, br s), 6.75-6.83 (1H,m), 6.98-7.08 (2H, m), 7.29 (2H, d, J=8.8 Hz), 7.34 (2H, d, J=8.8 Hz).

MS (m/z): 431 (M⁺+H)

HRMS (EI): as C₂₁H₂₆ClF₂O₃S (M⁺+H)

Calculated: 431.1259

Found: 431.1237

Example 22 1-[(4-Chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-3-octanol(Isomer 22-A and Isomer 22-B)

In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexanesolution, 0.701 ml, 1.10 mmol) was added to a tetrahydrofuran (5 ml)solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene(303 mg, 1.00 mmol) obtained in Example 5. The temperature of theresulting mixture was raised to room temperature. After cooling to −78°C., a trifluoroborane-ether complex (0.133 ml, 1.05 mmol) and1,2-epoxyheptane (0.163 ml, 1.20 mmol) were added dropwise to thereaction mixture. The mixture was stirred at room temperature for 2days. Water was added to the reaction mixture, followed by extractionwith diethyl ether. The extracts were combined, washed successively witha saturated aqueous solution of sodium bicarbonate, water and brine,dried over MgSO₄, and then concentrated. The residue thus obtained waspurified by medium-pressure chromatography on a silica gel column (20%ethyl acetate-hexane), whereby a low-polarity isomer, an isomer mixtureand a high-polarity isomer were obtained as a first fraction, a secondfraction and a third fraction, respectively, each as a colorless solid.The low-polarity isomer and high-polarity isomer were recrystallizedfrom hexane to yield the title Isomer 22-A (low-polarity) (98.0 mg,24%), and the title Isomer 22-B (high-polarity) (199 mg, 48%), each ascolorless needle crystals.

Isomer 22-A

Melting point: 84.0-84.5° C.

IR (ATR) ν: 3533, 2933, 2860, 1574, 1495, 1429, 1278, 1240, 1182, 1142,1092, 1080, 1014, 962, 885, 829, 766, 737, 710, 681, 619, 526, 476 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (3H, t, J=6.8 Hz), 1.20-1.50 (8H, m),1.57 (1H, d, J=5.1 Hz), 2.07 (1H, ddd, J=14.7, 8.1, 6.8 Hz), 2.70 (1H,ddd, J=14.7, 6.8, 4.6 Hz), 3.93-4.01 (1H, m), 4.85 (1H, t, J=6.8 Hz),6.77 (1H, td, J=9.0, 4.4 Hz), 6.91-6.98 (1H, m), 7.24-7.30 (1H, m), 7.36(2H, d, J=8.5 Hz), 7.51 (2H, d, J=8.5 Hz).

MS (m/z): 417 (M⁺+H).

HRMS (FAB) for C₂₀H₂₄ClF₂O₃S (M⁺+H)

Calculated: 417.1103

Analyzed: 417.1102

Elemental Analysis for C₂₀H₂₃ClF₂O₃S.0.25H₂O

Calculated: C, 57.00%; H, 5.62%; Cl, 8.41%; F, 9.02%; S, 7.61%.

Analyzed: C, 57.18%; H, 5.38%; Cl, 8.57%; F, 9.22%; S, 7.79%.

Isomer 22-B

Melting point: 123.0-123.5° C.

IR (ATR) ν: 3502, 2925, 2858, 1583, 1496, 1410, 1304, 1275, 1213, 1184,1149, 1086, 1045, 1014, 958, 910, 829, 796, 752, 725, 710, 627, 552,503, 467 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.87 (3H, t, J=7.1 Hz), 1.20-1.60 (9H, m),2.21-2.30 (1H, m), 2.41 (1H, ddd, J=13.9, 10.5, 3.4 Hz), 3.23-3.32 (1H,m), 4.94 (1H, dd, J=11.7, 2.9 Hz), 6.85 (1H, td, J=9.0, 4.4 Hz),6.96-7.03 (1H, m), 7.23-7.29 (1H, m), 7.39 (2H, d, J=8.5 Hz), 7.55 (2H,d, J=8.5 Hz).

MS (m/z) 417 (M⁺+H).

HRMS (FAB) for C₂₀H₂₄ClF₂O₃S (M⁺+H)

Calculated: 417.1103

Analyzed: 417.1122

Elemental Analysis for C₂₀H₂₃ClF₂O₃S.0.25H₂O

Calculated: C, 57.00%; H, 5.62%; Cl, 8.41%; F, 9.02%; S, 7.61%.

Analyzed: C, 57.16%; H, 5.34%; Cl, 8.55%; F, 9.18%; S, 7.82%.

Example 232-[S-Chloro-1-[(4-chlorophenyl)sulfonyl]pentyl]-1,4-difluorobenzene

Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57Mhexane solution, 3.52 ml) was added to a dimethoxyethane solution (30ml) of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (1.52g, 5.02 mmol) obtained in Example 5. The temperature of the reactionmixture was elevated to room temperature, at which stirring wasconducted for 15 minutes. After cooling the reaction mixture to −78° C.,4-chloro-1-iodobutane (672 μl, 5.52 mmol) was added thereto and themixture was stirred at room temperature for 24 hours. A saturatedammonium chloride solution was added to the reaction mixture, followedby extraction with diethyl ether. The extracts were combined, washedsuccessively with water, a saturated aqueous solution of sodiumthiosulfate and brine, dried over MgSO₄, and then distilled underreduced pressure to remove the solvent. The residue thus obtained wasrecrystallized from hexane, whereby the title compound (1.64 g, 83%) wasobtained as colorless needle crystals.

IR (ATR) ν: 2945, 1583, 1495, 1475, 1311, 1277, 1230, 1149, 1142, 1082,1014, 872, 822, 793, 752, 708, 629, 557, 532, 465 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.33-1.48 (2H, m), 1.72-1.87 (2H, m),2.08-2.18 (1H, m), 2.43-2.52 (1H, m), 3.44-3.53 (2H, m), 4.52 (1H, ddd,J=11.5, 3.9, 1.2 Hz), 6.84 (1H, td, J=9.0, 4.4 Hz), 6.96-7.02 (1H, m),7.23-7.28 (1H, m), 7.39 (2H, d, J=8.8 Hz), 7.53 (2H, d, J=8.8 Hz).

MS (m/z): 393 (M⁺+H).

Elemental Analysis for C₁₇H₁₆Cl₂F₂O₂S

Calculated: C, 51.92%; H, 4.10%; Cl, 18.03%; F, 9.66%; S, 8.15%.

Found: C, 51.33%; H, 4.07%; Cl, 17.64%; F, 9.72%; S, 8.25%.

Example 241-[5-[(4-Chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)pentyl]pyrrolidinehydrochloride

To a solution of2-[5-chloro-1-[(4-chlorophenyl)sulfonyl]pentyl]-1,4-difluorobenzene (200mg, 0.509 mmol) in acetonitrile (6 ml) were added pyrrolidine (213 μl,2.55 mmol), potassium carbonate (73.7 mg, 0.534 mmol) and potassiumiodide (15 mg). The resulting mixture was heated at 70° C. for 18 hours.The temperature of the reaction mixture was cooled back to roomtemperature. The residue thus obtained was partitioned between water andmethylene chloride. After separation of the organic layer, the waterlayer was extracted with methylene chloride. The organic layer and theextract were combined, washed with water and brine, dried over MgSO₄,and then concentrated. The crude product thus obtained was subjected toa short column (SiO₂, methylene chloride-methanol, 10:1). The resultingoil was dissolved in ethanol. After addition of 1N hydrochloricacid-ethanol (2 ml) to the resulting solution, the mixture wasconcentrated. The solid substance thus obtained was recrystallized fromethyl acetate, whereby the title compound (128 mg, 54%) was obtained asa pale yellow solid.

Melting point: 167.0-170.5° C.

IR (ATR) ν: 2960, 2565, 2453, 1583, 1495, 1321, 1277, 1211, 1173, 1145,1084, 1011, 879, 820, 787, 754, 721, 708, 627, 557, 540, 467 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.31-1.47 (2H, m), 1.93-2.30 (6H, m),2.42-2.51 (1H, m), 2.66-2.78 (2H, m), 2.87-3.03 (2H, m), 3.76 (2H, brs), 4.51 (1H, dd, J=10.7, 4.4 Hz), 6.85 (1H, td, J=8.8, 4.4 Hz),6.96-7.03 (1H, m), 7.22 (1H, ddd, J=8.8, 5.4, 3.2 Hz), 7.40 (2H, d,J=8.3 Hz), 7.54 (2H, d, J=8.3 Hz), 12.54 (1H, br s).

MS (m/z): 428 (M⁺+H).

Elemental Analysis for C₂₁H₂₄ClF₂NO₂S.HCl

Calculated: C, 54.31%; H, 5.43%; Cl, 15.27%; F, 8.18%; N, 3.02%; S,6.90%.

Analyzed: C, 54.19%; H, 5.37%; Cl, 15.07%; F, 8.10%; N, 3.21%; S, 6.98%.

Example 25 Ethyl3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propionate

Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57Mhexane solution, 7.01 ml) was added to a dimethoxyethane solution (50ml) of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (3.03g, 10.0 mmol) obtained in Example 5. The temperature of the reactionmixture was raised to room temperature, at which stirring was conductedfor 15 minutes. After cooling to −78° C., bromoethyl acetate (1.33 ml,12.0 mmol) was added to the reaction mixture. The mixture was stirred atroom temperature for 3 hours. To the reaction mixture was added asaturated ammonium chloride solution, followed by extraction withdiethyl ether. The extracts were combined, washed successively withwater, a saturated aqueous solution of sodium thiosulfate, and brine,dried over MgSO₄, and then distilled under reduced pressure to removethe solvent. The residue thus obtained was recrystallized from hexane,whereby the title compound (1.95 g, 50%) was obtained as colorlessneedle crystals.

Melting point: 99.5-100.5° C.

IR (ATR) ν: 3078, 2952, 1734, 1587, 1493, 1419, 1377, 1327, 1279, 1213,1149, 1047, 1014, 829, 779, 754, 727, 611, 542, 453 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.15 (3H, t, J=7.1 Hz), 3.08 (1H, dd, J=16.6, 10.3Hz), 3.46 (1H, dd, J=16.6, 4.6 Hz), 3.99-4.12 (2H, m), 5.06 (1H, dd,J=10.3, 4.6 Hz), 6.85 (1H, td, J=9.0, 4.4 Hz), 6.96-7.02 (1H, m), 7.19(1H, ddd, J=8.6, 5.4, 3.2 Hz), 7.42 (2H, d, J=8.8 Hz), 7.56 (2H, d,J=8.8 Hz).

MS (m/z): 389 (M⁺+H).

Elemental Analysis for C₁₇H₁₅ClF₂O₄S

Calculated: C, 52.51%; H, 3.89%; Cl, 9.12%; F, 9.77%; S, 8.25%.

Found: C, 52.33%; H, 3.86%; Cl, 9.10%; F, 9.88%; S, 8.37%.

Example 262-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylthio)pentyl]-1,4-difluorobenzene

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (0.94 g, 3.1mmol) obtained in Example 5 was dissolved in toluene (15 ml). Afteraddition of 4-(methylthio)-1-butanol (0.25 ml, 2.1 mmol) andcyanomethylenetri-n-butylphosphorane (1.0 g, 4.1 mmol), the resultingmixture was heated under reflux for 14 hours under an argon atmosphere.The reaction mixture was allowed to cool down. Then,4-(methylthio)-1-butanol (0.25 ml, 2.1 mmol) was added, followed byheating under reflux for 6 hours under an argon atmosphere. The reactionmixture was allowed to cool down and then, concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=10:1) to yield a colorless oil. Theresulting colorless oil was solidified with hexane, whereby the titlecompound (0.55 g, 44%) was obtained as a white powder.

Melting point: 103-106° C.

IR (ATR) ν: 3066, 2960, 2935, 1583, 1493, 1147, 1082, 1012, 893, 829,752, 625, 542, 465 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.23-1.45 (2H, m), 1.50-1.75 (2H, m), 2.04(3H, s), 2.04-2.20 (1H, m), 2.35-2.60 (3H, m), 4.52 (1H, dd, J=11.5, 2.4Hz), 6.78-6.88 (1H, m), 6.95-7.01 (1H, m), 7.20-7.30 (1H, m), 7.38 (2H,dm, J=8.4 Hz), 7.53 (2H, dm, J=8.4 Hz).

MS (m/z): 405, 407 (M⁺+H).

HRMS (FAB) for C₁₈H₂₀ClF₂O₂S₂ (M⁺+H)

Calculated: 405.0561

Found: 405.0581

Example 272-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]-1,4-difluorobenzene(Compound A) and2-[1-[(4-chlorophenyl)sulfonyl]-5-(methylsulfinyl)pentyl]-1,4-difluorobenzene(Compound B)

In methylene chloride (30 ml) was dissolved2-[1-[(4-chlorophenyl)sulfonyl]-5-(methylthio)pentyl]-1,4-difluorobenzene(500 mg, 1.23 mmol). Under ice cooling, 3-chloroperbenzoic acid (340 mg,1.97 mmol) was added to the resulting solution. The mixture was stirredat room temperature for 14 hours. After concentration of the reactionmixture under reduced pressure, the residue was subjected to silica gelchromatography. From the fraction eluted with hexane:ethyl acetate=10:1,a white solid was obtained. The solid was then washed with diethylether/methylene chloride to yield the title compound A (211 mg, 39%) asa white powder. Further, from the fraction eluted with the methylenechloride:methanol=40:1, a white solid was obtained. The solid was washedwith diethyl ether/methylene chloride, whereby the title compound B (144mg, 39%) was obtained as a white powder.

Compound A

Melting point: 145-148° C.

IR (ATR) ν: 1496, 1317, 1292, 1273, 1149, 1124, 1086, 829, 756, 631,544, 523, 499, 478, 465 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.38-1.70 (2H, m), 1.80-2.00 (2H, m),2.05-2.22 (1H, m), 2.45-2.60 (1H, m), 2.88 (3H, s), 2.96 (2H, tm, J=7.0Hz), 4.51 (1H, dm, J=7.6 Hz), 6.80-6.90 (1H, m), 6.95-7.05 (1H, m),7.20-7.35 (1H, m), 7.39 (2H, d, J=8.7 Hz), 7.53 (2H, d, J=8.7 Hz).

MS (m/z): 437, 439 (M⁺+H).

Elemental Analysis for C₁₈H₁₉ClF₂O₄S₂

Calculated: C, 49.48%; H, 4.38%; Cl, 8.11%; F, 8.70%; S, 14.68%.

Found: C, 49.50%; H, 4.28%; Cl, 8.05%; F, 8.77%; S, 14.70%.

Compound B

Melting point: 126-129° C.

IR (ATR) ν: 1495, 1475, 1277, 1147, 1086, 1012, 833, 752, 625, 540, 465cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.32-1.70 (2H, m), 1.75-1.93 (2H, m),2.08-2.22 (1H, m), 2.46-2.75 (3H, m), 2.54 (3H, S), 4.52 (1H, dd,J=11.4, 2.4 Hz), 6.80-6.90 (1H, m), 6.94-7.04 (1H, m), 7.20-7.30 (1H,m), 7.39 (2H, dd, J=8.5, 1.8 Hz), 7.53 (2H, dd, J=8.5, 2.7 Hz).

MS (m/z): 421, 423 (M⁺+H).

Elemental Analysis for C₁₈H₁₉ClF₂O₃S₂

Calculated: C, 51.36%; H, 4.55%; Cl, 8.42%; F, 9.03%; S, 15.24%.

Found: C, 51.36%; H, 4.49%; Cl, 8.35%; F, 9.00%; S, 15.24%.

Example 282-[1-[(4-Chlorophenyl)sulfonyl]-5-vinyloxypentyl]-1,4-difluorobenzene

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (0.94 g, 3.1mmol) obtained in Example 5 was dissolved in toluene (30 ml). Afteraddition of 4-vinyloxy-1-butanol (0.51 ml, 4.2 mmol) andcyanomethylenetri-n-butylphosphorane (1.0 g, 4.1 mmol), the resultingmixture was heated under reflux for 3 days under an argon atmosphere.The reaction mixture was allowed to cool down and then concentratedunder reduced pressure. The residue thus obtained was purified by silicagel chromatography (hexane:ethyl acetate=10:1) to yield a white solid.The resulting white solid was washed with hexane, whereby the titlecompound (0.97 g, 78%) was obtained as a white powder.

Melting point: 54-56° C.

IR (ATR) ν: 2943, 1618, 1495, 1475, 1308, 1198, 1147, 1080, 1012, 962,899, 829, 750, 623, 559, 544, 467 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.25-1.45 (2H, m), 1.55-1.80 (2H, m),2.05-2.22 (1H, m), 2.40-2.55 (1H, m), 3.62 (2H, t, J=6.2 Hz), 3.96 (1H,dd, J=6.8, 2.1 Hz), 4.12 (1H, dd, J=14.4, 2.1 Hz), 4.53 (1H, dd, J=11.5,2.7 Hz), 6.39 (1H, dd, J=14.4, 6.8 Hz), 6.80-6.90 (1H, m), 6.95-7.04(1H, m), 7.20-7.30 (1H, m), 7.39 (2H, d, J=8.6 Hz), 7.54 (2H, d, J=8.6Hz).

MS (m/z): 418, 420 (M⁺+NH₄).

Elemental Analysis for C₁₉H₁₉ClF₂O₃S

Calculated: C, 56.93%; H, 4.78%; Cl, 8.84%; F, 9.48%; S, 8.00%.

Found: C, 56.98%; H, 4.83%; Cl, 8.78%; F, 9.51%; S, 8.13%.

Example 295-[(4-Chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-1-pentanol

In methanol (30 ml) was dissolved2-[1-[(4-chlorophenyl)sulfonyl]-5-vinyloxypentyl]-1,4-difluorobenzene(0.90 g, 2.3 mmol). After addition of p-toluenesulfonic acid monohydrate(20 mg, 0.11 mmol), the resulting mixture was stirred at roomtemperature for 14 hours. The reaction mixture was concentrated underreduced pressure. The residue was purified by silica gel chromatography(hexane:ethyl acetate=3:2) to yield a white solid. The resulting whitesolid was washed with diisopropyl ether, whereby the title compound(0.73 g, 85%) was obtained as a white powder.

Melting point: 84-86° C.

IR (ATR) ν: 3325, 2941, 2866, 1583, 1496, 1313, 1151, 1084, 825, 752,629, 534 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.18-1.29 (1H, m), 1.29-1.40 (2H, m),1.40-1.70 (2H, m), 2.08-2.22 (1H, m), 2.42-2.55 (1H, m), 3.55-3.67 (2H,m), 4.53 (1H, dd, J=11.4, 3.8 Hz), 6.78-6.88 (1H, m), 6.93-7.03 (1H, m),7.20-7.30 (1H, m), 7.39 (2H, d, J=8.5 Hz), 7.53 (2H, d, J=8.5 Hz).

MS (m/z): 375, 377 (M⁺+H).

Elemental Analysis for C₁₇H₁₇ClF₂O₃S.0.25H₂O

Calculated: C, 53.83%; H, 4.65%; Cl, 9.35%; F, 10.02%; S, 8.45%.

Found: C, 53.73%; H, 4.63%; Cl, 9.35%; F, 10.03%; S, 8.55%.

Example 302-[1-[(4-Chlorophenyl)sulfonyl]cyclopentyl]-1,4-difluorobenzene

In toluene (10 ml) was dissolved5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-1-pentanol (100 mg,0.267 mmol). After addition of cyanomethylenetri-n-butylphosphorane (130mg, 0.539 mmol), the mixture was heated under reflux for 2 days under anargon atmosphere. The reaction mixture was allowed to cool down andthen, added with cyanomethylenetri-n-butylphosphorane (130 mg, 0.539mmol). The mixture was heated under reflux for 3 days under an argonatmosphere. The reaction mixture was allowed to cool down and thenconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel chromatography (hexane:ethyl acetate=15:1) toyield a white solid. The resulting white solid was washed with hexane,whereby the title compound (35 mg, 37%) was obtained as a white powder.

Melting point: 153-155° C.

IR (ATR) ν: 2968, 1581, 1489, 1304, 1277, 1138, 1082, 827, 752, 606,569, 519, 467 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.70-1.85 (2H, m), 2.05-2.20 (2H, m),2.22-2.35 (2H, m), 2.88-3.00 (2H, m), 6.75-6.83 (1H, m), 6.95-7.05 (2H,m), 7.35 (4H, s).

MS (m/z): 374, 376 (M⁺+NH₄).

Elemental Analysis for C₁₇H₁₅ClF₂O₂S

Calculated: C, 57.22%; H, 4.24%; Cl, 9.94%; F, 10.65%; S, 8.99%.

Found: C, 56.87%; H, 4.14%; Cl, 10.28%; F, 10.44%; S, 9.05%.

Example 312-[6-(t-Butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]hexyl]-1,4-difluorobenzene

In toluene (30 ml) was dissolved the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (0.94 g, 3.1mmol) obtained in Example 5, followed by the addition of5-(t-butyldimethylsilyloxy)-1-pentanol (1.1 ml, 4.6 mmol) andcyanomethylenetri-n-butylphosphorane (1.0 g, 4.1 mmol). The resultingmixture was heated under reflux for 14 hours under an argon atmosphere.The reaction mixture was allowed to cool down and then concentratedunder reduced pressure. The residue thus obtained was purified by silicagel chromatography (hexane:ethyl acetate-15:1), whereby the titlecompound (1.4 g, 87%) was obtained as a colorless oil.

IR (ATR) ν: 2929, 2856, 1583, 1496, 1325, 1151, 1088, 835, 775, 754, 629cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.01 (6H, s), 0.86 (9H, s), 1.18-1.60 (6H,m), 2.04-2.17 (1H, m), 2.38-2.50 (1H, m), 3.54 (2H, t, J=6.1 Hz), 4.53(1H, dd, J=11.5, 2.7 Hz), 6.78-6.88 (1H, m), 6.93-7.03 (1H, m),7.20-7.30 (1H, m), 7.38 (2H, d, J=8.5 Hz), 7.53 (2H, d, J=8.5 Hz).

MS (m/z): 503, 505 (M⁺+H).

Example 32 6-[(4-Chlorophenyl)sulfonyl]-6-(2,5-difluorophenyl)-1-hexanol

In tetrahydrofuran (30 ml) was dissolved2-[6-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]hexyl]-1,4-difluorobenzene(0.70 g, 1.4 mmol). Under ice cooling, a tetrahydrofuran solution(11.0M, 4.2 ml, 4.2 mmol) of tetrabutylammonium fluoride was added andthe mixture was stirred at room temperature for 1 hour. After additionof water (1.0 ml) to the reaction mixture, the mixture was concentratedunder reduced pressure. The residue thus obtained was purified by silicagel chromatography (hexane:ethyl acetate=3:2) to yield a white solid.The resulting white solid was washed with hexane, whereby the titlecompound (0.47 g, 86%) was obtained as a white powder.

Melting point: 98-99° C.

IR (ATR) ν: 3575, 2929, 1495, 1279, 1146, 1082, 1014, 833, 752, 627,541, 467 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.18-1.62 (7H, m), 2.04-2.18 (1H, m),2.40-2.53 (1H, m), 3.59 (2H, dd, J=11.5, 6.4 Hz), 4.52 (1H, dd, J=11.5,2.7 Hz), 6.78-6.88 (1H, m), 6.94-7.04 (1H, m), 7.20-7.30 (1H, m), 7.38(2H, d, J=8.4 Hz), 7.53 (2H, d, J=8.4 Hz).

MS (m/z): 389, 391 (M⁺+H).

Elemental Analysis for C₁₈H₁₉ClF₂O₃S

Calculated: C, 55.60%; H, 4.92%; Cl, 9.12%; F, 9.77%; S, 8.25%.

Found: C, 55.38%; H, 4.75%; Cl, 9.09%; F, 9.81%; S, 8.34%.

Example 332-[1-[(4-Chlorophenyl)sulfonyl]cyclohexyl]-1,4-difluorobenzene

In toluene (20 ml) was dissolved6-[(4-chlorophenyl)sulfonyl]-6-(2,5-difluorophenyl)-1-hexanol (200 mg,0.514 mmol). After addition of cyanomethylenetri-n-butylphosphorane (500mg, 2.07 mmol), the resulting mixture was heated under reflux for 4 daysunder an argon atmosphere. The reaction mixture was allowed to cool downand then concentrated under reduced pressure. The residue thus obtainedwas purified by silica gel chromatography (hexane:ethyl acetate=20:1) toyield a white solid. The resulting solid was washed withhexane/methylene chloride, whereby the title compound (97 mg, 51%) wasobtained as a white powder.

Melting point: 137-139° C.

IR (ATR) ν: cm⁻¹. 2933, 2862, 1495, 1309, 1144, 1082, 885, 814, 750,619, 559, 464 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.10-1.45 (3H, m), 1.61 (1H, dm, J=12.0 Hz),1.81 (2H, br d, J=13.4 Hz), 2.09 (2H, br t, J=13.0 Hz), 2.55-2.95 (2H,m), 6.84 (1H, ddd, J=12.2, 9.0, 4.9 Hz), 7.00-7.11 (2H, m), 7.36 (2H,s), 7.36 (2H, s).

MS (m/z): 388, 390 (M⁺+NH₄).

Elemental Analysis for C₁₈H₁₇ClF₂O₃S

Calculated: C, 58.30%; H, 4.62%; Cl, 9.56%; F, 10.25%; S, 8.65%.

Found: C, 58.01%; H, 4.49%; Cl, 9.58%; F, 10.35%; S, 8.82%.

Example 342-[1-[(4-Chlorophenyl)sulfonyl]-3-(2-vinyloxyethoxy)propyl]-1,4-difluorobenzene

In toluene (30 ml) was dissolved the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (520 mg, 1.72mmol) obtained in Example 5. After addition of2,2-(2-vinyloxyethoxy)ethanol (0.270 ml, 2.10 mmol) andcyanomethylenetri-n-butylphosphorane (500 mg, 2.07 mmol), the mixturewas heated under reflux for 24 hours under an argon atmosphere. Thereaction mixture was then allowed to cool down. After addition of2-(2-vinyloxyethoxy)-ethanol (0.170 ml, 1.25 mmol) andcyanomethylenetri-n-butylphosphorane (300 mg, 1.24 mmol), the mixturewas heated under reflux for 12 hours under an argon atmosphere. Thereaction mixture was allowed to cool down and then concentrated underreduced pressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=7:1) to yield a white solid. Theresulting white solid was washed with hexane, whereby the title compound(140 mg, 20%) was obtained as a white powder.

Melting point: 55-56° C.

IR (ATR) ν: 2927, 2877, 1621, 1496, 1323, 1198, 1144, 1084, 1012, 829,752, 633, 542, 469 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 2.20-2.35 (1H, m), 2.70-2.85 (1H, m), 3.28(1H, td, J=9.5, 4.6 Hz), 3.40-3.50 (1H, m), 3.54-3.68 (2H, m), 3.71 (2H,t, J=4.6 Hz), 3.99 (1H, dd, J=6.7, 2.1 Hz), 4.14 (1H, dd, J=14.3, 2.1Hz), 4.81 (1H, dd, J=10.9, 4.0 Hz), 6.41 (1H, dd, J=14.3, 6.7 Hz), 6.84(1H, td, J=9.0, 4.4 Hz), 6.94-7.04 (1H, m), 7.18-7.30 (1H, m), 7.39 (2H,dm, J=8.3 Hz), 7.56 (2H, dm, J=8.3 Hz).

MS (m/z): 417, 419 (M⁺+H).

Elemental Analysis for C₁₉H₁₉ClF₂O₄S

Calculated: C, 54.74%; H, 4.59%; Cl, 8.50%; F, 9.11%; S, 7.69%.

Found: C, 54.54%; H, 4.46%; Cl, 8.46%; F, 9.02%; S, 7.81%.

Example 352-[3-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propoxy]ethanol

In methanol (10 ml) was dissolved2-[1-[(4-chlorophenyl)sulfonyl]-3-(2-vinyloxyethoxy)propyl]-1,4-difluorobenzene(123 mg, 0.295 mmol). P-toluenesulfonic acid monohydrate (2.0 mg, 0.011mmol) was added and the mixture was stirred at room temperature for 4hours. After concentration under reduced pressure, the residue waspurified by silica gel chromatography (methylene chloride:methanol=50:1)to yield a white solid. The resulting white solid was washed withhexane, whereby the title compound (80 mg, 70%) was obtained as a whitepowder.

Melting point: 41-46° C.

IR (ATR) ν: 3467, 2943, 1495, 1315, 1149, 1086, 1061, 829, 762, 521cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.78-1.80 (1H, m), 2.22-2.36 (1H, m),2.75-2.88 (1H, m), 3.20-3.40 (2H, m), 3.42-3.52 (1H, m), 3.57-3.73 (3H,m), 4.81 (1H, dd, J=10.9, 3.8 Hz), 6.84 (1H, td, J=9.0, 4.4 Hz),6.94-7.04 (1H, m), 7.22-7.30 (1H, m), 7.39 (2H, dm, J=8.4 Hz), 7.55 (2H,dm, J=8.4 Hz).

MS (m/z): 391, 393 (M⁺+H).

Elemental Analysis for C₁₇H₁₇ClF₂O₄S

Calculated: C, 52.24%; H, 4.38%; Cl, 9.07%; F, 9.72%; S, 8.20%.

Found: C, 52.12%; H, 4.36%; Cl, 9.11%; F, 9.86%; S, 8.32%.

Example 362-[[(4-Chlorophenyl)sulfonyl](cylcohexyl)methyl]-1,4-difluorobenzene

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (240 mg,0.793 mmol) obtained in Example 5 was dissolved in toluene (20 ml). Tothe resulting solution were added cyclohexanol (0.11 ml, 1.0 mmol) andcyanomethylenetri-n-butylphosphorane (250 mg, 1.0 mmol). The resultingmixture was heated under reflux for 14 hours under an argon atmosphere.The reaction mixture was allowed to cool down and then, added withcyclohexanol (0.22 ml, 2.1 mmol) andcyanomethylenetri-n-butylphosphorane (500 mg, 2.08 mmol). The mixturewas heated under reflux for 14 hours under an argon atmosphere. Afterthe reaction mixture was allowed to cool down and concentrated underreduced pressure, the residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=30:1) to yield a white solid. Theresulting white solid was washed with hexane, whereby the title compound(188 mg, 62%) was obtained as a white powder.

Melting point: 107-109° C.

IR (ATR) ν: 2927, 2858, 1495, 1240, 1138, 1080, 874, 831, 796, 750, 708,615, 548, 507, 469, 444 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92-1.08 (1H, m), 1.08-1.22 (1H, m),1.22-1.50 (3H, m), 1.60-1.75 (3H, m), 1.75-1.88 (1H, m), 2.37 (1H, br d,J=12.5 Hz), 2.48-2.62 (1H, m), 4.44 (1H, d, J=7.6 Hz), 6.68-6.80 (1H,m), 6.86-6.95 (1H, m), 7.30 (2H, dm, J=8.6 Hz), 7.38-7.52 (1H, m), 7.49(2H, dm, J=8.6 Hz).

MS (m/z): 402, 404 (M⁺+NH₄).

Elemental Analysis for C₁₉H₁₉ClF₂O₂S

Calculated: C, 59.29%; H, 4.98%; Cl, 9.21%; F, 9.87%; S, 8.33%.

Found: C, 59.11%; H, 4.93%; Cl, 9.18%; F, 9.82%; S, 8.49%.

Example 372-[6-Bromo-1-[(4-chlorophenyl)sulfonyl]hexyl]-1,4-difluorobenzene

Sodium hydride (60% dispersion in oil, 15 mg, 0.38 mmol) was added totetrahydrofuran (10 ml). Under ice cooling, the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330mmol) obtained in Example 5 was added. After stirring the reactionmixture at room temperature for 30 minutes, 1,5-dibromopentane (0.10 ml,0.74 mmol) was added. The reaction mixture was stirred at roomtemperature for 3 days, followed by the addition of sodium hydride (60%dispersion in oil, 15 mg, 0.38 mmol) under ice cooling. The resultingmixture was stirred at room temperature for 15 minutes and then addedwith 1,5-dibromopentane (0.10 ml, 0.74 mmol). The mixture was stirred atroom temperature for 14 hours and then concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=10:1) to yield a white solid. Theresulting white solid was washed with hexane, whereby the title compound(51 mg, 30%) was obtained as a white powder.

Melting point: 77-79° C.

IR (ATR) ν: 2937, 1495, 1147, 1084, 1014, 893, 833, 795, 752, 708, 627,559, 536, 465 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.20-1.35 (2H, m), 1.37-1.55 (2H, m),1.74-1.88 (2H, m), 2.05-2.20 (1H, m), 2.40-2.53 (1H, m), 3.34 (2H, td,J=6.6, 1.3 Hz), 4.51 (1H, dd, J=11.5, 2.7 Hz), 6.83 (1H, td, J=9.0, 4.6Hz), 6.94-7.04 (1H, m), 7.20-7.30 (1H, m), 7.38 (2H, d, J=8.7 Hz), 7.53(2H, d, J=8.7 Hz).

MS (m/z): 468, 470 (M⁺+NH₄).

Elemental Analysis for C₁₈H₁₈BrClF₂O₂S

Calculated: C, 47.86%; H, 4.02%; Br 17.69%; Cl, 7.85%; F, 8.41%; S,7.10%.

Found: C, 47.80%; H, 3.83%; Br 17.67%; Cl, 7.86%; F, 8.65%; S, 7.25%.

Referential Example 2 4-(t-Butyldiphenylsilyloxy)-1-methyl-1-butanol

In N,N-dimethylformamide (200 ml) were dissolved 1,4-pentanediol (10.0g, 96.0 mmol) and imidazole (6.6 g, 96.9 mmol). Under ice cooling,t-butyl chlorodiphenylsilane (25.2 ml, 96.4 mmol) was added dropwise.After completion of the dropwise addition, the reaction mixture wasstirred at room temperature for 2 days. To the reaction mixture wasadded diethyl ether, followed by washing with water. The organic layerwas dried over anhydrous magnesium sulfate. After filtration, theresidue obtained by concentrating the filtrate under reduced pressurewas purified by silica gel chromatography (hexane:ethyl acetate=5:1),whereby the title compound (32.0 g, 97%) was obtained as a colorlessoil.

IR (ATR) ν: 3350, 2929, 2856, 1427, 1105, 822, 739, 698, 609, 501 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.05 (9H, S), 1.19 (3H, d, J=6.3 Hz),1.46-1.72 (4H, m), 2.02-2.08 (1H, m), 3.69 (2H, t, J=6.0 Hz), 3.78-3.90(1H, m), 7.30-7.50 (6H, m), 7.62-7.88 (4H, m).

MS (m/z): 343 (M⁺+H).

Example 382-[5-(t-Butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-2-methylpentyl]-1,4-difluorobenzene(Isomer 38-A and Isomer 38-B)

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (0.94 g, 3.1mmol) obtained in Example 5 was dissolved in toluene (30 ml), followedby the addition of 4-(t-butyldiphenylsilyloxy)-1-methyl-1-butanol (1.40g, 4.1 mmol) and cyanomethylenetri-n-butylphosphorane (1.0 g, 4.1 mmol).The resulting mixture was heated under reflux for 2 days under an argonatmosphere. The reaction mixture was allowed to cool down and then,cyanomethylenetri-n-butylphosphorane (1.0 g, 4.1 mmol) was addedthereto. Under an argon atmosphere, the resulting mixture was heatedunder reflux for 3 days. After the reaction mixture was allowed to cooldown, the residue obtained by concentrating the mixture under reducedpressure was purified by silica gel chromatography (hexane:ethylacetate=60:1), whereby the title Isomer 38-A (low-polarity) (0.71 g,37%) and the title isomer 38-B (high-polarity) (0.45 g, 23%) wereobtained, each as a colorless oil.

Isomer 38-A

IR (ATR) ν: 2931, 2858, 1495, 1322, 1149, 1109, 1088, 1012, 822, 752,700, 613, 503, 488, 469 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.02 (9H, s), 1.09 (3H, d, J=6.8 Hz),1.26-1.42 (1H, m), 1.50-1.80 (3H, m), 2.74-2.86 (1H, m), 3.64 (2H, t,J=5.7 Hz), 4.51 (1H, d, J=5.6 Hz), 6.78 (1H, td, J=9.1, 4.6 Hz),6.90-7.00 (1H, m), 7.30-7.48 (8H, m), 7.50-7.58 (3H, m), 7.60-7.70 (4H,m).

MS (m/z): 627 (M⁺+H).

Isomer 38-B

IR (ATR) ν: 2931, 2858, 1495, 1147, 1107, 1088, 822, 752, 729, 700, 613,559, 503, 471 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (9H, s), 1.00-1.20 (1H, m), 1.37 (3H, d,J=6.8 Hz), 1.40-1.64 (3H, m), 2.60-2.74 (1H, m), 3.48-3.60 (2H, m), 4.43(1H, br d, J=9.3 Hz), 6.69 (1H, td, J=9.0, 4.4 Hz), 6.84-6.93 (1H, m),7.24-7.45 (9H, m), 7.48 (2H, d, J=8.6 Hz), 7.52-7.62 (4H, m).

MS (m/z): 627 (M⁺+H).

Example 395-[(4-Chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-4-methyl-1-pentanol

The2-[5-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-2-methylpentyl]-1,4-difluorobenzene(Isomer 38-A) (710 mg, 1.13 mmol) obtained in Example 38 was dissolvedin methylene chloride (20 ml). Under ice cooling, hydrogenfluoride-pyridine (0.64 ml) was added dropwise. After completion of thedropwise addition, the reaction mixture was stirred at room temperaturefor 14 hours. To the reaction mixture was added a saturated aqueoussolution (20 ml) of sodium bicarbonate, followed by extraction withdiethyl ether. The organic layer was washed successively with 1Nhydrochloric acid, a saturated aqueous solution of sodium bicarbonateand brine, and dried over anhydrous magnesium sulfate. After filtration,the filtrate was concentrated under reduced pressure. The residue thusobtained was purified by silica gel chromatography (hexane:ethylacetate=2:1) to yield a colorless oil. The resulting colorless oil wassolidified with hexane, whereby the title compound (283 mg, 64%) wasobtained as a white powder.

Melting point: 84-86° C.

IR (ATR) ν: 3367, 2937, 1496, 1138, 1084, 1051, 1012, 829, 754, 729,708, 621, 561, 532, 471 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.07 (3H, d, J=6.8 Hz), 1.40-1.85 (5H, m),2.75-2.90 (1H, m), 3.64-3.75 (2H, m), 4.54 (1H, d, J=6.6 Hz), 6.77 (1H,td, J=9.0, 4.4 Hz), 6.90-7.00 (1H, m), 7.33 (2H, d, J=8.4 Hz), 7.43-7.60(1H, m), 7.51 (2H, d, J=8.4 Hz).

MS (m/z): 389, 391 (M⁺+H).

Elemental Analysis for C₁₈H₁₉ClF₂O₃S

Calculated: C, 55.60%; H, 4.92%; Cl, 9.12%; F, 9.77%; S, 8.25%.

Found: C, 55.42%; H, 4.83%; Cl, 9.10%; F, 9.85%; S, 8.30%.

Example 405-[(4-Chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-4-methyl-1-pentanol

The2-[5-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-2-methylpentyl]-1,4-difluorobenzene(Isomer 38-B) (450 mg, 0.717 mmol) obtained in Example 38 was dissolvedin methylene chloride (10 ml). Under ice cooling, hydrogenfluoride-pyridine (0.41 ml) was added dropwise. After completion of thedropwise addition, the reaction mixture was stirred at room temperaturefor 14 hours. To the reaction mixture was added a saturated aqueoussolution (20 ml) of sodium bicarbonate, followed by extraction withdiethyl ether. The organic layer was washed successively with 1Nhydrochloric acid, a saturated aqueous solution of sodium bicarbonateand brine and dried over anhydrous magnesium sulfate. After filtration,the residue obtained by concentrating the filtrate under reducedpressure was purified by silica gel chromatography (hexane:ethylacetate=2:1) to yield a colorless oil. The resulting colorless oil wassolidified with hexane, whereby the title compound (194 mg, 70%) wasobtained as a white powder.

Melting point: 67-69° C.

IR (ATR) ν: 3537, 2933, 2868, 1481, 1308, 1279, 1240, 1144, 1078, 822,802, 754, 712, 665, 613, 544, 469 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.08-1.22 (1H, m), 1.23 (1H, t, J=5.2 Hz),1.36 (3H, d, J=6.8 Hz), 1.45-1.70 (3H, m), 2.67-2.80 (1H, m), 3.50-3.65(2H, m), 4.45 (1H, d, J=8.3 Hz), 6.73 (1H, td, J=9.0, 4.6 Hz), 6.88-6.97(1H, m), 7.31 (2H, d, J=8.8 Hz), 7.34-7.48 (1H, m), 7.49 (2H, d, J=8.8Hz).

MS (m/z): 389, 391 (M⁺+H).

Elemental Analysis for C₁₈H₁₉ClF₂O₃S

Calculated: C, 55.60%; H, 4.92%; Cl, 9.12%; F, 9.77%; S, 8.25%.

Found: C, 55.48%; H, 4.84%; Cl, 9.01%; F, 9.76%; S, 8.32%.

Example 412-[5-Bromo-1-[(4-chlorophenyl)sulfonyl]-2-methylpentyl]-1,4-difluorobenzene

The5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-4-methyl-1-pentanol(290 mg, 0.746 mmol) obtained in Example 39 and carbon tetrabromide (290mg, 0.874 mmol) were dissolved in methylene chloride (8 ml). Whilestirring under ice cooling, a solution obtained by dissolvingtriphenylphosphine (230 mg, 0.877 mmol) in methylene chloride (2 ml) wasadded dropwise to the resulting solution. After completion of thedropwise addition, the reaction mixture was stirred at room temperaturefor 3 days. To the reaction mixture were added carbon tetrabromide (290mg, 0.874 mmol) and triphenylphosphine (230 mg, 0.877 mmol) under icecooling, followed by stirring at room temperature for 6 hours. Theresidue obtained by concentrating the reaction mixture under reducedpressure was purified by silica gel chromatography (hexane:ethylacetate=15:1), whereby the title compound (331 mg, 98%) was obtained asa colorless oil.

IR (ATR) ν: 2966, 1495, 1321, 1238, 1147, 1088, 1012, 789, 752, 729,712, 613, 559, 536, 471 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.07 (3H, d, J=6.8 Hz), 1.46-1.60 (1H, m),1.77-2.11 (3H, m), 2.74-2.90 (1H, m), 3.41 (2H, t, J=6.7 Hz), 4.49 (1H,d, J=6.6 Hz), 6.78 (1H, td, J=9.1, 4.6 Hz), 6.90-7.00 (1H, m), 7.33 (2H,d, J=8.7 Hz), 7.45-7.60 (1H, m), 7.52 (2H, d, J=8.7 Hz).

MS (m/z): 451, 453 (M⁺+H).

Example 422-[5-Bromo-1-[(4-chlorophenyl)sulfonyl]-2-methylpentyl]-1,4-difluorobenzene

The5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-4-methyl-1-pentanol(170 mg, 0.437 mmol) obtained in Example 40 and carbon tetrabromide (170mg, 0.648 mmol) were dissolved in methylene chloride (8 ml). Whilestirring under ice cooling, triphenylphosphine (135 mg, 0.515 mmol) wasadded to the resulting solution, followed by stirring at roomtemperature for 14 hours. To the reaction mixture were added carbontetrabromide (170 mg, 0.437 mmol) and triphenylphosphine (135 mg, 0.515mmol) under ice cooling. The reaction mixture was stirred at roomtemperature for 6 hours. The residue obtained by concentrating thereaction mixture under reduced pressure was purified by silica gelchromatography (hexane:ethyl acetate=10:1), whereby the title compound(192 mg, 97%) was obtained as a colorless oil.

IR (ATR) ν: 3091, 2966, 1496, 1296, 1246, 1142, 1080, 889, 839, 754,710, 627, 553, 513, 471 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.18-1.31 (1H, m), 1.37 (3H, d, J=6.8 Hz),1.50-1.70 (1H, m), 1.78-1.92 (2H, m), 2.62-2.80 (1H, m), 3.20-3.40 (2H,m), 4.44 (1H, d, J=8.5 Hz), 6.73 (1H, td, J=9.0, 4.5 Hz), 6.88-6.98 (1H,m), 7.30 (2H, d, J=8.6 Hz), 7.30-7.50 (1H, m), 7.49 (2H, d, J=8.6 Hz).

MS (m/z): 451, 453 (M⁺+H).

Example 432-[1-[(4-Chlorophenyl)sulfonyl]-2-methyl-5-(methylthio)pentyl]-1,4-difluorobenzene(Isomer 43-A and Isomer 43-B)

The2-[5-bromo-1-[(4-chlorophenyl)sulfonyl]-2-methylpentyl]-1,4-difluorobenzene(325 mg, 0.719 mmol) obtained in Example 41 and the2-[5-bromo-1-[(4-chlorophenyl)sulfonyl]-2-methylpentyl]-1,4-difluorobenzene(185 mg, 0.410 mmol) obtained in Example 42 were dissolved intetrahydrofuran (25 ml). To the resulting solution was added sodiumthiomethoxide (160 mg, 2.28 mmol) under ice cooling. After stirring atroom temperature for 14 hours, sodium thiomethoxide (190 mg, 2.71 mmol)was added to the resulting mixture under ice cooling. The residueobtained by concentrating the reaction mixture under reduced pressurewas purified by silica gel chromatography (hexane:ethyl acetate=30:1),whereby the title Isomer 43-A (low-polarity) (185 mg, 39%) and the titleIsomer 43-B (high-polarity) (186 mg, 39%) were obtained, each as acolorless oil.

Isomer 43-A

IR (ATR) ν: 2916, 1493, 1321, 1238, 1146, 1088, 1012, 789, 752, 712,613, 559, 536, 469 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.08 (3H, d, J=6.9 Hz), 1.40-1.54 (1H, m),1.55-1.85 (3H, m), 2.10 (3H, s), 2.50 (2H, t, J=7.2 Hz), 2.75-2.90 (1H,m), 4.51 (1H, d, J=6.1 Hz), 6.78 (1H, td, J=9.1, 4.4 Hz), 6.90-7.00 (1H,m), 7.33 (2H, d, J=8.6 Hz), 7.45-7.60 (1H, m), 7.52 (2H, d, J=8.6 Hz).

MS (m/z): 419, 421 (M⁺+H).

HRMS (FAB) for C₁₉H₂₂ClF₂O₂S₂ (M⁺+H)

Calculated: 419.0718

Found: 419.0733

Isomer 43-B

IR (ATR) ν: 2952, 2920, 1493, 1308, 1232, 1176, 1149, 1090, 827, 750,629, 590, 557, 532, 472 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.10-1.30 (1H, m), 1.37 (3H, d, J=6.6 Hz),1.50-1.65 (3H, m), 2.03 (3H, s), 2.30-2.50 (2H, m), 2.64-2.78 (1H, m),4.44 (1H, d, J=8.6 Hz), 6.73 (1H, td, J=9.0, 4.5 Hz), 6.86-6.98 (1H, m),7.30 (2H, d, J=8.6 Hz), 7.34-7.46 (1H, m), 7.48 (2H, d, J=8.6 Hz).

MS (m/z): 419, 421 (M⁺+H).

HRMS (FAB) for C₁₉H₂₂ClF₂O₂S₂ (M⁺+H)

Calculated: 419.0718

Found: 419.0715

Example 442-[1-[(4-Chlorophenyl)sulfonyl]-2-methyl-5-(methylsulfinyl)pentyl]-1,4-difluorobenzene

The2-[1-[(4-chlorophenyl)sulfonyl]-2-methyl-5-(methylthio)pentyl]-1,4-difluorobenzene(Isomer 43-A) (180 mg, 0.430 mmol) obtained in Example 43 was dissolvedin methylene chloride (10 ml). Under ice cooling, 3-chloroperbenzoicacid (89 mg, 0.52 mmol) was added, followed by stirring at roomtemperature for 14 hours. The residue obtained by concentrating thereaction mixture under reduced pressure was purified by silica gelchromatography (methylene chloride:methanol=40:1), whereby the titlecompound (172 mg, 92%) was obtained a colorless oil.

IR (ATR) ν: 2920, 1495, 1317, 1279, 1238, 1146, 1086, 1036, 829, 789,752, 712, 615, 559, 471 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.00-1.10 (3H, m), 1.50-1.75 (1H, m),1.78-2.10 (3H, m), 2.60 (1.5H, s), 2.60 (1.5H, s), 2.65-2.90 (3H, m),4.50 (1H, d, J=7.6 Hz), 6.77 (1H, td, J=9.2, 4.4 Hz), 6.90-7.00 (1H, m),7.32 (2H, d, J=8.5 Hz), 7.40-7.60 (1H, m), 7.50 (2H, d, J=8.5 Hz).

MS (m/z): 435, 437 (M⁺+H)

HRMS (FAB) for C₁₉H₂₂ClF₂O₃S₂ (M⁺+H)

Calculated: 435.0667

Found: 435.0655

Example 452-[1-[(4-Chlorophenyl)sulfonyl]-2-methyl-5-(methylsulfinyl)pentyl]-1,4-difluorobenzene

The2-[1-[(4-chlorophenyl)sulfonyl]-2-methyl-5-(methylthio)pentyl]-1,4-difluorobenzene(Isomer 43-B) (175 mg, 0.418 mmol) obtained in Example 43 was dissolvedin methylene chloride (10 ml). Under ice cooling, 3-chloroperbenzoicacid (87 mg, 0.50 mmol) was added. The resulting mixture was stirred atroom temperature for 14 hours. The residue obtained by concentrating thereaction mixture under reduced pressure was purified silica gelchromatography (methylene chloride:methanol=40:1) to yield a whitesolid. The resulting solid was washed with diethyl ether, whereby thetitle compound (118 mg, 65%) was obtained as a white powder.

Melting point: 107-112° C.

IR (ATR) ν: 3087, 2943, 1496, 1315, 1242, 1178, 1149, 1088, 1028, 829,731, 623, 584, 538, 457 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.15-1.40 (4H, m), 1.45-2.00 (3H, m),2.50-2.85 (3H, m), 2.54 (3H, s), 4.46 (1H, d, J=8.1 Hz), 6.78 (1H, td,J=9.0, 4.7 Hz), 6.90-7.00 (1H, m), 7.32 (2H, d, J=8.4 Hz), 7.35-7.50(1H, m), 7.49 (2H, d, J=8.4 Hz).

MS (m/z): 435, 437 (M⁺+H).

Elemental Analysis for C₁₉H₂₁ClF₂O₃S₂

Calculated: C, 52.47%; H, 4.87%; Cl, 8.15%; F, 8.74%; S, 14.74%.

Found: C, 52.44%; H, 4.85%; Cl, 8.17%; F, 8.79%; S, 14.63%.

Example 462-[1-[(4-Chlorophenyl)sulfonyl]-2-methyl-5-(methylsulfonyl)pentyl]-1,4-difluorobenzene

The2-[1-[(4-chlorophenyl)sulfonyl]-2-methyl-5-(methylsulfinyl)pentyl]-1,4-difluorobenzene(76 mg, 0.18 mmol) obtained in Example 44 was dissolved in methylenechloride (5 ml). Under ice cooling, 3-chloroperbenzoic acid (36 mg, 0.21mmol) was added. The resulting mixture was stirred at room temperaturefor 2 hours. The residue obtained by concentrating the reaction mixturewas purified by silica gel chromatography (methylenechloride:methanol=100:1) to yield a pale yellowish brown oil. Theresulting pale yellowish brown oil was solidified with diethylether/methylene chloride, whereby the title compound (61 mg, 77%) wasobtained as a white powder.

Melting point: 115-117° C.

IR (ATR) ν: 3078, 2937, 1493, 1311, 1286, 1230, 1151, 1136, 1086, 831,754, 729, 712, 623, 542, 519, 471, 459 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.03 (3H, d, J=7.1 Hz), 1.60-1.80 (1H, m),1.85-2.20 (3H, m), 2.70-2.90 (1H, m), 2.94 (3H, s), 3.07 (2H, t, J=7.8Hz), 4.49 (1H, d, J=7.8 Hz), 6.76 (1H, td, J=9.1, 4.5 Hz), 6.90-7.00(1H, m), 7.32 (2H, d, J=8.5 Hz), 7.35-7.60 (1H, m), 7.49 (2H, d, J=8.5Hz).

MS (m/z): 451, 453 (M⁺+H).

Elemental Analysis for C₁₉H₂₁ClF₂O₄S₂

Calculated: C, 50.61%; H, 4.96%; Cl, 7.86%; F, 8.43%; S, 14.22%.

Found: C, 50.57%; H, 4.74%; Cl, 7.85%; F, 8.58%; S, 14.25%.

Example 472-[1-[(4-Chlorophenyl)sulfonyl]-2-methyl-5-(methylsulfonyl)pentyl]-1,4-difluorobenzene

The2-[1-[(4-chlorophenyl)sulfonyl]-2-methyl-5-(methylsulfinyl)pentyl]-1,4-difluorobenzene(66 mg, 0.15 mmol) obtained in Example 45 was dissolved in methylenechloride (5 ml). Under ice cooling, 3-chloroperbenzoic acid (32 mg, 0.19mmol) was added. The resulting mixture was stirred at room temperaturefor 3 hours. The residue obtained by concentrating the reaction mixtureunder reduced pressure was purified by silica gel chromatography(methylene chloride:methanol=100:1) to yield a white solid. Theresulting white solid was washed with diethyl ether/methylene chloride,whereby the title compound (52 mg, 76%) was obtained as a white powder.

Melting point: 142-144° C.

IR (ATR) ν: 3082, 2937, 1495, 1317, 1290, 1234, 1151, 1130, 1092, 831,769, 754, 731, 712, 625, 544, 525, 503, 472, 449, 417 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.15-1.40 (1H, m), 1.32 (3H, d, J=6.6 Hz),1.40-2.05 (3H, m), 2.65-3.10 (3H, m), 2.88 (3H, s), 4.46 (1H, d, J=7.1Hz), 6.77 (1H, td, J=9.1, 4.6 Hz), 6.90-7.00 (1H, m), 7.32 (2H, d, J=8.4Hz), 7.35-7.50 (1H, m), 7.49 (2H, d, J=8.4 Hz).

MS (m/z): 451, 453 (M⁺+H).

Elemental Analysis for C₁₉H₂₁ClF₂O₄S₂

Calculated: C, 50.61%; H, 4.69%; Cl, 7.86%; F, 8.43%; S, 14.22%.

Found: C, 50.48%; H, 4.59%; Cl, 7.93%; F, 8.57%; S, 14.09%.

Example 484-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)tetrahydropyrane

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (1.0 g, 3.30mmol) obtained in Example 5 was dissolved in tetrahydrofuran (70 ml). At−78° C., a hexane solution (1.57M, 5.3 ml, 8.3 mmol) of n-butyl lithiumwas added dropwise. After completion of the dropwise addition, thereaction mixture was stirred at −78° C. for 10 minutes and then stirredfor another 30 minutes under ice cooling. At −78° C., 2-bromoethyl ether(0.55 ml, 3.9 mmol) was added dropwise to the reaction mixture. Aftercompletion of the dropwise addition, the temperature of the reactionmixture was elevated to room temperature over 14 hours. Water (2.0 ml)was added to the reaction mixture. The residue obtained by concentratingthe resulting mixture under reduced pressure was purified by silica gelchromatography (hexane:ethyl acetate=5:1) to yield a white solid. Theresulting white solid was washed with diisopropyl ether/methylenechloride, whereby the title compound (317 mg, 26%) was obtained as awhite powder.

Melting point: 157-160° C.

IR (ATR) ν: 2966, 2862, 1496, 1309, 1188, 1149, 1086, 1012, 899, 841,808. 750, 710, 629, 592, 569, 536, 515, 471 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 2.40-2.80 (4H, m), 3.32 (2H, t, J=12.5 Hz),4.02 (2H, dt, J=11.8, 3.3 Hz), 6.82-6.95 (1H, m), 7.05-7.17 (2H, m),7.38 (2H, s), 7.39 (2H, s).

MS (m/z): 373, 375 (M⁺+H).

Elemental Analysis for C₁₇H₁₅ClF₂O₃S

Calculated: C, 54.77%; H, 4.06%; Cl, 9.51%; F, 10.19%; S, 8.60%.

Found: C, 54.55%; H, 4.00%; Cl, 9.69%; F, 10.33%; S, 8.64%.

Example 495-[(4-Chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)pentyl=1-pyrrolidinecarboxylato

To a methylene chloride (6 ml) solution of the5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-1-pentanol (390 mg,1.04 mmol) obtained in Example 29 were added triethylamine (152 μl, 1.09mmol) and 4-nitrophenyl chloroformate (220 mg, 1.09 mmol). The resultingmixture was stirred at room temperature for 24 hours. The reactionmixture was concentrated, whereby crude5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)pentyl=4-nitrophenyl=carbonato(759 mg) was obtained. The resulting crude5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)pentyl=4-nitrophenyl=carbonato(268 mg) was dissolved in methylene chloride (4 ml), followed by theaddition of triethylamine (76.7 μl, 0.551 mmol) and pyrrolidine (46.0μl, 0.551 mmol). The mixture was stirred at room temperature for 15hours. The reaction mixture was concentrated and the residue wasdissolved in diethyl ether. The resulting solution was washedsuccessively with a saturated aqueous solution of potassium bicarbonate,a saturated aqueous solution of ammonium chloride, water and brine,dried over MgSO₄, and then concentrated. The residue thus obtained waspurified by medium-pressure chromatography on a silica gel column (40%ethyl acetate-hexane), whereby the title compound (128 mg, 74%) wasobtained as a pale brown oil.

IR (ATR) ν: 3086, 2954, 2875, 1689, 1583, 1496, 1423, 1321, 1176, 1147,1084, 1012, 874, 752, 536, 467 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.26-1.38 (2H, m), 1.54-1.73 (2H, m),1.78-1.90 (4H, m), 2.09-2.20 (1H, m), 2.42-2.52 (1H, m), 3.19-3.40 (4H,m), 3.96-4.05 (2H, m), 4.52 (1H, dd, J=11.5, 2.7 Hz), 6.83 (1H, td,J=9.1, 4.4 Hz), 6.94-7.01 (1H, m), 7.21-7.28 (1H, m), 7.38 (2H, d, J=8.6Hz), 7.52 (2H, d, J=8.6 Hz).

MS (m/z) 472 (M⁺+H).

HRMS (FAB) for C₂₂H₂₄ClF₂NO₄S (M⁺+H)

Calculated: 472.1161

Analyzed: 472.1124

Referential Example 3 4-(Methylsulfonyl)-1-butanol

While stirring under ice cooling, 3-chloroperbenzoic acid (3.04 g, 17.6mmol) was added to a methylene chloride (100 ml) solution of4-(methylthio)-1-butanol (1.01 g, 8.40 mmol). At room temperature, themixture was stirred for 20 hours. After completion of the reaction wasconfirmed, the solvent was concentrated under reduced pressure. To theresidue were added diethyl ether and water to separate the water layer.The resulting water layer was concentrated under reduced pressure.Methylene chloride was added to the residue. The mixture was dried overanhydrous sodium sulfate, and then the solvent was concentrated underreduced pressure. The residue was subjected to chromatography on asilica gel column. From the fraction eluted with methanol:methylenechloride (=1:20), the title compound (1.21 g, 95%) was obtained as apale yellow oil.

IR (ATR) ν: 3494, 2931, 2877, 1457, 1413, 1282, 1122, 1054, 1029, 966,827, 765, 518, 462 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.55-1.91 (3H, m), 1.91-2.11 (2H, m), 2.92(3H, s), 3.09 (2H, t, J=7.9 Hz), 3.72 (2H, t, J=6.1 Hz).

MS (m/z): 153 (M⁺+H).

Referential Example 4 4-(Methylsulfinyl)-1-butanol

While stirring under ice cooling, sodium periodate (1.24 g, 5.80 mmol)was added to a mixed solution of 4-(methylthio)-1-butanol (465 mg, 3.87mmol) in tetrahydrofuran (15 ml) and water (3 ml). At room temperature,the resulting mixture was stirred for 21.5 hours. After completion ofthe reaction was confirmed, the reaction mixture was diluted withmethylene chloride and then subjected to Celite filtration. The filtratewas concentrated under reduced pressure. To the residue was addedmethylene chloride. The resulting mixture was dried over anhydroussodium sulfate and then, the solvent was concentrated under reducedpressure. The residue thus obtained was subjected to chromatography on asilica gel column, whereby from the fraction eluted withmethanol:methylene chloride (=1:10), the title compound (160 mg, 30%)was obtained as a pale yellow oil.

IR (ATR) ν: 3369, 2937, 2867, 1658, 1452, 1411, 1054, 1006, 941, 694cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.40-1.55 (1H, br), 1.68-1.83 (2H, m),1.93-2.08 (2H, m), 2.92 (3H, s), 3.09 (2H, t, J=7.9 Hz), 3.72 (2H, t,J=5.5 Hz).

MS (m/z): 137 (M⁺+H).

Example 50 1-Chloro-4-(benzylsulfonyl)benzene

Sodium 4-chlorobenzenesulfinate (306 mg, 1.54 mmol) and benzyl bromide(0.18 ml, 1.54 mmol) were added to n-butanol (15 ml). The resultingmixture was stirred at 70° C. for 5 hours. After cooling to roomtemperature, the solvent was concentrated under reduced pressure. To theresidue were added ethyl acetate. The resulting mixture was washedsuccessively with water and brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was subjected tochromatography on a silica gel column, whereby from the fraction elutedwith hexane:ethyl acetate (=8:1), the title compound (299 mg, 73%) wasobtained as a white solid.

Melting point: 147.5-148.5° C.

IR (ATR) ν: 3060, 3029, 2994, 2942, 1583, 1571, 1492, 1475, 1454, 1396,1311, 1294, 1274, 1147, 1087, 1014, 977, 917, 831, 773, 757, 696, 642,532, 462 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 4.31 (2H, s), 7.23-7.38 (4H, m), 7.38-7.46(2H, m), 7.49-7.58 (2H, m).

MS (m/z) 267 (M⁺+H).

Example 51 1-Chloro-4-(5-methylsulfonyl-1-phenylpentyl)sulfonylbenzene

Under an argon atmosphere, a toluene (20 ml) solution of1-chloro-4-(benzylsulfonyl)benzene (90 mg, 0.337 mmol), the4-(methylsulfonyl)-1-butanol (69 mg, 0.453 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n-butylphosphorane (233 mg, 0.965 mmol)was heated under reflux for 21 hours. After cooling to room temperature,the reaction mixture was concentrated under reduced pressure. Theresidue was subjected to medium-pressure chromatography on a silica gelcolumn. From the fraction eluted with hexane:ethyl acetate (=2:1), thetitle compound (44 mg, 33%) was obtained as a white solid.

Melting point: 151-152° C.

IR (ATR) ν: 2937, 2867, 1577, 1467, 1396, 1319, 1270, 1203, 1147, 1087,1058, 1014, 962, 842, 802, 755, 696, 632, 565, 530, 474, 420 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.34-1.52 (2H, m), 1.79-1.97 (2H, m),2.13-2.28 (2H, m), 2.45-2.58 (1H, m), 2.86 (3H, s), 2.89-3.00 (2H, m),4.01 (1H, dd, J=11.2, 3.9 Hz), 7.08 (1H, d, J=8.1 Hz), 7.22-7.47 (8H,m).

MS (m/z): 401 (M⁺+H).

Elemental Analysis for C₁₈H₂₁ClO₄S₂

Calculated: C, 53.92%; H, 5.28%; Cl, 8.84%; S, 16.00%.

Found: C, 53.92%; H, 5.21%; Cl, 9.05%; S, 15.88%.

Example 52 1-Chloro-4-(5-methylsulfinyl-1-phenylpentyl)sulfonylbenzene

A toluene (15 ml) solution of the 4-chloro-1-(benzylsulfonyl)benzene(122 mg, 0.457 mmol) obtained in Example 50, the4-(methylsulfinyl)-1-butanol (81 mg, 0.595 mmol) obtained in ReferentialExample 4 and cyanomethylenetri-n-butylphosphorane (221 mg, 0.916 mmol)was heated under reflux for 2 days under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue was subjected to medium-pressurechromatography on a silica gel column, whereby from the fraction elutedwith methylene chloride:methanol (=100:1), a white solid was obtained.The resulting white solid was recrystallized from diethyl ether to givethe title compound (20 mg, 11%) as white needle crystals.

Melting point: 98.5-99.5° C.

IR (ATR) ν: 2935, 2856, 1575, 1473, 1455, 1392, 1309, 1276, 1143, 1081,1016, 946, 829, 794, 755, 694, 624, 563, 520, 464 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 32-1.50 (2H, m), 1.70-1.90 (2H, m), 2.15-2.28(1H, m), 2.45-2.70 (2H, m), 2.52 (3H, s), 4.02 (1H, dd, J=11.4, 3.8 Hz),7.05-7.12 (1H, m), 7.20-7.47 (8H, m).

MS (m/z): 385 (M⁺+H)

Elemental Analysis for C₁₈H₂₁ClO₃S₂

Calculated: C, 56.16%; H, 5.50%; Cl, 9.21%; S, 16.66%.

Found: C, 56.03%; H, 5.37%; Cl, 9.29%; S, 16.69%.

Example 531-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]-2-fluorobenzene

To sodium 4-chlorobenzenesulfinate (203 mg, 1.02 mmol) and2-fluorobenzyl bromide (124 μL, 1.02 mmol) were added n-butanol (5 ml).The resulting mixture was stirred at 70° C. for 5 hours. After coolingto room temperature, the solvent was concentrated under reducedpressure. To the residue was added methylene chloride and from theresulting mixture, the insoluble matter was filtered off. The filtratewas concentrated under reduced pressure. The residue was washed withdiisopropyl ether to yield white powder (111 mg).

A toluene (10 ml) solution of the resulting white powder (35 mg), the4-(methylsulfonyl)-1-butanol (38 mg, 0.250 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n-butylphosphorane (60 mg, 0.246 mmol)was heated under reflux for 17.5 hours under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue was subjected to medium-pressurechromatography on a silica gel column. From the fraction eluted withhexane:ethyl acetate (=11:1), the title compound was obtained as a whitesolid (46 mg).

Melting point: 167-168° C.

IR (ATR) ν: 2948, 2867, 1614, 1579, 1488, 1455, 1396, 1319, 1290, 1268,1230, 1199, 1149, 1126, 1085, 1014, 962, 829, 792, 767, 752, 713, 628,572, 532, 495, 458, 430 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.38-1.52 (2H, m), 1.80-1.98 (2H, m),2.16-2.29 (1H, m), 2.48-2.60 (1H, m), 2.87 (3H, s), 2.96 (2H, t, J=7.9Hz), 4.55 (1H, dd, J=11.0, 4.2 Hz), 6.85 (1H, td, J=9.1, 1.1 Hz),7.17-7.39 (4H, m), 7.43-7.58 (3H, m).

MS (m/z): 419 (M⁺+H).

Elemental Analysis for C₁₈H₂₀ClFO₄S₂

Calculated: C, 51.61%; H, 4.81%; Cl, 8.46%; F, 4.53%; S, 15.31%.

Found: C, 51.65%; H, 4.74%; Cl, 8.33%; F, 4.50%; S, 15.20%.

Example 541-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]-3-fluorobenzene

Sodium 4-chlorobenzenesulfinate (216 mg, 1.09 mmol) and 3-fluorobenzylbromide (136 μL, 1.09 mmol) were added to n-butanol (5 ml). Theresulting mixture was stirred at 70° C. for 5 hours. After cooling toroom temperature, the solvent was concentrated under reduced pressure.To the residue was added methylene chloride and from the resultingmixture, the insoluble matter was filtered off. The filtrate wasconcentrated under reduced pressure. The residue thus obtained waswashed with diisopropyl ether to yield a white powder (208 mg).

Then, a toluene (10 ml) solution of the resulting white powder (59 mg),the 4-(methylsulfonyl)-1-butanol (65 mg, 0.427 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (100 mg,0.414 mmol) was heated under reflux for 29.5 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected tomedium-pressure chromatography on a silica gel column, whereby from thefraction eluted with hexane:ethyl acetate (=2:3), the title compound wasobtained as a white solid (71 mg).

Melting point: 116-117° C.

IR (ATR) ν: 2942, 2875, 1590, 1469, 1394, 1317, 1295, 1270, 1241, 1201,1145, 1083, 1012, 964, 875, 840, 798, 769, 752, 705, 686, 634, 592, 541,530, 512, 491, 464 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.34-1.52 (2H, m), 1.78-1.99 (2H, m),2.09-2.22 (1H, m), 2.41-2.56 (1H, m), 2.81-3.03 (2H, m), 2.88 (3H, s),4.01 (1H, dd, J=11.2, 3.9 Hz), 6.83 (1H, d, J=7.6 Hz), 6.90 (1H, d,J=9.3 Hz), 7.03 (1H, td, J=8.1, 2.2 Hz), 7.23 (1H, td, J=7.9, 6.0 Hz),7.32-7.50 (4H, m).

MS (m/z): 419 (M⁺+H).

Elemental Analysis for C₁₈H₂₀ClFO₄S₂

Calculated: C, 51.61%; H, 4.81%; Cl, 8.31%; F, 4.53%; S, 15.31%.

Found: C, 51.68%; H, 4.72%; Cl, 8.31%; F, 4.52%; S, 15.30%.

Example 551-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]-4-fluorobenzene

Sodium 4-chlorobenzenesulfinate (183 mg, 0.921 mmol) and 4-fluorobenzylbromide (112 mL, 0.921 mmol) were added to n-butanol (5 ml). Theresulting mixture was stirred at 70° C. for 6 hours. After cooling toroom temperature, the solvent was concentrated under reduced pressure.To the residue was added ethyl acetate, and from the resulting mixture,the insoluble matter was filtered off. The filtrate was concentratedunder reduced pressure. The residue was washed with diisopropyl ether toyield a white powder (150 mg).

Then, a toluene (10 ml) solution of the resulting white powder (57 mg),the 4-(methylsulfonyl)-1-butanol (62 mg, 0.407 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (97 mg,0.400 mmol) was heated under reflux for 17 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected tomedium-pressure chromatography on a silica gel column, whereby from thefraction eluted with hexane:ethyl acetate (=2:3), the title compound wasobtained as a white solid (58 mg).

Melting point: 141-142.5° C.

IR (ATR) ν: 2937, 2865, 1606, 1577, 1508, 1467, 1394, 1317, 1292, 1270,1236, 1147, 1126, 1085, 1014, 962, 838, 825, 755, 721, 626, 574, 553,514, 482, 455 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.35-1.50 (2H, m), 1.80-1.97 (2H, m),2.09-2.21 (1H, m), 2.43-2.56 (1H, m), 2.88 (3H, s), 2.90-3.00 (2H, m),4.01 (1H, dd, J=11.2, 3.9 Hz), 6.97 (2H, t, J=8.5 Hz), 7.03-7.11 (2H,m), 7.36-7.48 (4H, m).

MS (m/z): 419 (M⁺+H).

Elemental Analysis for C₁₈H₂₀ClFO₄S₂

Calculated: C, 51.61%; H, 4.74%; Cl, 8.46%; F, 4.53%; S, 15.31%.

Found: C, 51.74%; H, 4.74%; Cl, 8.28%; F, 4.53%; S, 15.36%.

Example 562-[1-[(4-Chlorophenyl)sulfonyl]-1-methylthio]methyl-1,4-difluorobenzene

Under a nitrogen atmosphere, the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (82.8 mg, 0.27mmol) obtained in Example 5 was added to a N,N-dimethylformamidesuspension (2.0 ml) of sodium hydride (12 mg, 0.30 mmol) at roomtemperature. The resulting mixture was stirred for 10 minutes. To thereaction mixture was added methyl methanethiosulfonate (28.1 mg, 0.27mmol) and the mixture was stirred for another 30 minutes. The reactionmixture was added with a saturated aqueous sodium bicarbonate solution(10 ml), followed by extraction with diethyl ether. The organic layerwas washed with water and brine, and dried over anhydrous magnesiumsulfate. After filtration, the residue obtained by concentrating thefiltrate under reduced pressure was purified by silica gelchromatography (hexane:diethyl ether=4:1), whereby the title compound(36 mg, 38%) was obtained as a white solid.

Melting point: 128-129° C.

IR (ATR) ν: 1489, 1315, 1234, 1147, 1078, 829 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 2.47 (3H, s), 5.22 (1H, s), 6.88 (1H, m),6.97 (1H, m), 7.13 (1H, m), 7.41 (2H, m), 7.60 (2H, m).

MS (m/z): 173 (M⁺-SO₂Ar).

Elemental Analysis for C₁₄H₁₁ClF₂O₂S₂

Calculated: C, 48.21%; H, 3.18%; S, 18.39%; Cl, 10.16%; F, 10.89%.

Found: C, 48.41%; H, 3.28%; S, 17.88%; Cl, 10.41%; F, 10.57%.

Example 572-[1-[(4-Chlorophenyl)sulfonyl]-1-phenylthio]methyl-1,4-difluorobenzene

In a similar manner to that employed in Example 56 except for the use ofphenyl phenylthiosulfonate, the title compound was synthesized.

Melting point: 84-85° C.

IR (ATR) ν: 1492, 1319, 1149, 1086, 825 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 5.53 (1H, s), 6.91 (1H, m), 7.01 (1H, m),7.23-7.31 (4H, m), 7.35-7.40 (4H, m), 7.65 (2H, m), 7.65 (2H, m),7.40-7.35 (4H, m), 7.31-7.23 (4H, m), 7.01 (1H, m), 6.91 (1H, m), 5.53(1H, s).

MS (m/z): 235 (M⁺-SO₂Ar).

Elemental Analysis for C₁₉H₁₃ClF₂O₂S₂

Calculated: C, 55.54%; H, 3.19%; S, 15.61%; Cl, 8.63%; F, 9.25%.

Found: C, 55.50%; H, 3.18%; S, 15.51%; Cl, 8.40%; F, 9.03%.

Example 58 Benzyl[(4-chlorophenyl)sulfonyl-(2,5-difluorophenyl)methyl]carbamate

To a tetrahydrofuran solution (0.4 ml) of benzyl carbamate (151 mg, 1.0mmol) were added water (1.0 ml), sodium chlorobenzenesulfinate (199 mg,1.0 mmol), 2,5-difluorobenzaldehyde (142 mg, 1.0 mmol) and formic acid(0.24 ml). The resulting mixture was stirred for 19 hours at roomtemperature. To the reaction mixture having a white precipitate formedtherein were added diethyl ether and water. The precipitate wascollected by filtration and washed sufficiently with diethyl ether,whereby the title compound (251 mg, 51%) was obtained.

Melting point: 183-184° C.

IR (ATR) ν: 1726, 1518, 1495, 1319, 1230, 1147, 831 cm⁻¹.

¹H-NMR (400 MHz, DMSO-d₆) δ: 4.91 (1H, d, J=12.4 Hz), 4.97 (1H, d,J=12.4 Hz), 6.25 (1H, d, J=10.4 Hz), 7.2-7.45 (7H, m), 7.70 (2H, d,J=8.4 Hz), 7.71 (1H, m), 7.78 (2H, d, J=8.4 Hz), 9.33 (1H, d, J=10.4Hz).

MS (m/z): 275 (M⁺-SO₂Ar).

Referential Example 5 Benzyl 2,5-difluorophenylacrylate

Under a nitrogen atmosphere, dicyclohexyl carbodiimide (206 mg, 1.0mmol) was added to a methylene chloride solution (10 ml) of2,5-difluorophenylacrylic acid (184 mg, 1 mmol), benzyl alcohol (104 ml,1 mmol), and N,N-dimethylaminopyridine (36 mg, 0.3 mmol) at roomtemperature and the resulting mixture was stirred for 17 hours. Afterconcentration of the reaction mixture under reduced pressure, 10 ml ofhexane-diethyl ether (4:1) was added to the residue. The precipitatethus formed was filtered. The filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography(hexane:ethyl acetate=5:1), whereby the title compound (242 mg, 88%) wasobtained.

Melting point: 45-46° C.

IR (ATR) ν: 1712, 1641, 1305, 1167, 692 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 5.24 (S, 2H), 6.54 (d, 1H, J=16.4 Hz), 7.03(m, 2H), 7.18 (m, 1H), 7.37 (m, 5H), 7.77 (d, 1H, J=16.4 Hz).

Example 59 Benzyl3-(4-chlorophenylsulfonyl)-3-(2,5-difluorophenyl)propionate

Under a nitrogen atmosphere, a hexane solution (1.57M, 0.05 ml) ofn-butyl lithium was added to a tetrahydrofuran (10 ml) solution ofbenzyl 2,5-difluorophenylacrylate (108 mg, 0.39 mmol) and4-chlorobenzenethiol (57 mg, 0.39 mmol) at room temperature. Theresulting mixture was stirred for 1 hour. After concentrating thereaction mixture under reduced pressure, the residue was subjected tosilica gel chromatography. The fraction eluted with hexane:diethyl ether(=10:1) was concentrated under reduced pressure.

Then, the residue was dissolved in methanol (10 ml). To the resultingsolution were added water (1.0 ml), hexaammonium heptamolybdatetetrahydrate (5.0 mg), and 30% aqueous hydrogen peroxide (2 ml) at roomtemperature, followed by stirring for 48 hours. The reaction mixture wasdiluted with ethyl acetate (50 ml) and then, washed sufficiently withwater and brine. The organic layer was dried over anhydrous magnesiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue thus obtained was purified by silica gel chromatography(hexane:ethyl acetate=8:1), whereby the title compound (33 mg, 19%) wasobtained.

Melting point: 127-128° C.

IR (ATR) ν: 1734, 1498, 1317, 1211, 1170, 1149, 748 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 3.12 (dd, 1H, J=10.4, 16.8 Hz), 3.48 (dd, 1H,J=4.4, 16.8 Hz), 4.98 (d, 1H, J=12.0 Hz), 5.02 (m, 1H), 5.03 (d, 1H,J=12.0 Hz), 6.79 (m, 1H), 6.81 (m, 1H), 7.1-7.2 (m, 3H), 7.23 (m, 3H),7.38 (d, 2H, J=8.4 Hz), 7.52 (d, 2H, J=8.4 Hz).

Elemental Analysis for C₂₂H₁₇ClF₂O₄S.0.5H₂O

Calculated: C, 57.46%; H, 3.91%; S, 6.97%; Cl, 7.70%; F, 8.26%.

Found C, 57.60%; H, 3.89%; S, 7.02%; Cl, 7.83%; F, 8.31%.

MS (m/z): 450 (M⁺)

HRMS (EI): as C₂₂H₁₇ClF₂O₄S (M⁺)

Calculated: 450.0504

Found: 450.0496

Example 602-[1-[(4-Chlorophenyl)sulfonyl]-2-pentylcyclopropyl]-1,4-difluorobenzene

Under a nitrogen atmosphere, triethylamine (36.4 μl, 0.262 mmol) andmethanesulfonyl chloride (18.6 μl, 0.240 mmol) were added to a methylenechloride (4 ml) solution of the isomer mixture (91.0 mg, 0.218 mmol) ofthe 1-[(4-chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-3-octanolobtained in Example 22 at 0° C. The resulting mixture was stirred at 0°C. for 2 hours. The reaction mixture was diluted with methylenechloride, washed with water and brine, dried over MgSO₄, and thenconcentrated. The residue thus obtained was subjected to chromatographyon a short silica gel column. The fraction eluted with hexane:ethylacetate (=3:1) was concentrated under reduced pressure to yield acolorless oil.

The resulting colorless oil was dissolved in tetrahydrofuran (4 ml). Inan argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexanesolution, 0.127 ml, 0.200 mmol) was added to the resulting solution,followed by stirring at −78° C. for 3 hours. The reaction mixture wasadded with a saturated aqueous ammonium chloride solution, followed byextraction with diethyl ether. The extracts were combined, washedsuccessively with water and brine, dried over MgSO₄, and thenconcentrated. The residue thus obtained was purified by medium-pressurechromatography on a silica gel column (8% ethyl acetate-hexane), wherebythe title compound (48.1 mg, 66%) was obtained as a colorless oil.

IR (ATR) ν: 2929, 2925, 2858, 1585, 1496, 1317, 1250, 1176, 1146, 1090,1014, 889, 827, 796, 760, 715, 602, 565, 478 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.43-0.62 (1H, m), 0.83-0.95 (3H, m),1.13-1.70 (7.66H, m), 1.82-1.93 (0.33H, m), 1.99 (0.33H, dd, J=9.8, 5.4Hz), 2.07 (0.66H, dd, J=9.8, 5.9 Hz), 2.26-2.40 (1H, m), 6.74-6.84 (1H,m), 6.91 (0.33H, td, J=9.0, 4.4 Hz), 6.98-7.05 (1H, m), 7.13 (0.66H,ddd, J=8.6, 5.6, 3.2 Hz), 7.35-7.50 (4H, m).

MS (m/z) 399 (M⁺+H).

HRMS (FAB) for C₂₀H₂₂ClF₂O₂S (M⁺+H)

Calculated: 399.0997

Found: 399.1006

Example 61 t-Butyl3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propionate

Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57Mhexane solution, 7.01 ml) was added dropwise to a dimethoxyethanesolution (50 ml) of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (3.03 g, 10.0mmol) obtained in Example 5. The temperature of the reaction mixture wasraised to room temperature. Then, the reaction mixture was cooled to−78° C. After the addition of t-butyl bromoacetate (1.48 ml, 10.0 mmol),the resulting mixture was stirred at room temperature for 3 hours. Thereaction mixture was added with a saturated aqueous ammonium chloridesolution, followed by extraction with diethyl ether. The extracts werecombined, washed successively with water and brine, dried over MgSO₄,and then distilled to remove the solvent. The residue thus obtained wassubjected to chromatography on a short silica gel column (hexane-ethylacetate 3:1). The solid thus obtained was recrystallized from hexane,whereby the title compound (3.30 g, 79%) was obtained as a colorlesssolid.

Melting point: 140.5-142.0° C.

IR (ATR) ν: 3074, 2983, 1722, 1585, 1496, 1427, 1396, 1369, 1275, 1257,1215, 1142, 1086, 955, 835, 781, 750, 712, 665, 606, 559, 467 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.28 (9H, s), 3.00 (1H, dd, J=16.4, 10.7 Hz),3.37 (1H, dd, J=16.4, 4.4 Hz), 5.00 (1H, dd, J=10.7, 4.4 Hz), 6.85 (1H,td, J=9.0, 4.6 Hz), 6.96-7.03 (1H, m), 7.19 (1H, ddd, J=8.8, 5.6, 3.2Hz), 7.41 (2H, d, J=8.3 Hz), 7.50 (2H, d, J=8.3 Hz).

MS (m/z): 417 (M⁺+H).

HRMS (FAB) for C₁₉H₁₉ClF₂O₄S (M⁺+H)

Calculated: 416.0661

Found: 416.0690

Elemental Analysis for C₁₉H₁₉ClF₂O₄S

Calculated: C, 54.74%; H, 4.59%; Cl, 8.50%; F, 9.11%; S, 7.69%.

Found: C, 54.67%; H, 4.55%; Cl, 8.54%; F, 9.17%; S, 7.80%.

Example 62 3-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propionicacid

At 0° C., trifluoroacetic acid (10 ml) was added to a methylene chloride(30 ml) solution of t-butyl3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propionate (3.10 g,7.43 mmol). The resulting mixture was stirred at room temperature for 2hours. To the residue obtained by concentrating the reaction mixture wasadded toluene and the resulting mixture was concentrated. The residuethus obtained was recrystallized from ethyl acetate-hexane, whereby thetitle compound (2.29 g, 85%) was obtained as colorless needle crystals.

Melting point: 152.0-153.0° C.

IR (ATR) ν: 2956, 1707, 1576, 1496, 1427, 1396, 1321, 1255, 1217, 1115,1086, 1012, 914, 893, 829, 795, 756, 708, 619, 536, 459 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 3.13 (1H, dd, J=17.1, 10.4 Hz), 3.53 (1H, dd,J=17.1, 4.6 Hz), 5.02 (1H, dd, J=10.4, 4.6 Hz), 6.85 (1H, td, J=9.0, 4.6Hz), 6.96-7.03 (1H, m), 7.18 (1H, ddd, J=8.5, 5.4, 3.2 Hz), 7.41 (2H, d,J=8.8 Hz), 7.55 (2H, d, J=8.8 Hz).

MS (m/z): 360 (M⁺).

HRMS (EI): as C₁₅H₁₁ClF₂O₄S (M⁺)

Calculated: 360.0035

Found: 360.0026

Elemental Analysis for C₁₅H₁₁ClF₂O₄S

Calculated: C, 49.94%; H, 3.07%; Cl, 9.83%; F, 10.53%; S, 8.89%.

Found: C, 49.74%; H, 2.99%; Cl, 9.88%; F, 10.63%; S, 8.98%.

Example 631-Chloro-2-[1-[(4-chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene

Sodium 4-chlorobenzenesulfinate (205 mg, 1.03 mmol) and 2-chlorobenzylbromide (134 μl, 1.03 mmol) were added to dimethoxyethane (5 ml). Theresulting mixture was stirred at 70° C. for 6 hours. After cooling toroom temperature, the solvent was concentrated under reduced pressure.To the residue was added ethyl acetate and from the resulting mixture,the insoluble matter was filtered off. The filtrate was concentratedunder reduced pressure. The residue was washed with hexane to yield awhite powder (231 mg).

A toluene (10 ml) solution of the resulting white powder (92 mg), the4-(methylsulfonyl)-1-butanol (96 mg, 0.631 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n-butylphosphorane (148 mg, 0.614 mmol)was heated under reflux for 20 hours under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue was subjected to medium-pressurechromatography on a silica gel column, whereby from the fraction elutedwith hexane:ethyl acetate (=1:1), the title compound (74 mg) wasobtained as a colorless oil.

IR (ATR) ν: 2931, 2873, 1573, 1475, 1442, 1394, 1313, 1276, 1133, 1083,1033, 1012, 962, 908, 829, 794, 748, 713, 684, 626, 568, 518, 464 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.33-1.52 (2H, m), 1.79-1.98 (2H, m),2.15-2.30 (1H, m), 2.50-2.60 (1H, m), 2.86 (3H, s), 2.94 (2H, t, J=7.9Hz), 4.86 (1H, dd, J=11.0, 3.9 Hz), 7.17-7.29 (3H, m), 7.29-7.38 (2H,m), 7.41-7.50 (2H, m), 7.67 (1H, d, J=7.8 Hz).

MS (m/z): 435 (M⁺+H)

HRMS (FAB) for C₁₈H₂₁O₄Cl₂S₂ (M⁺+H)

Calculated: 435.0258

Found: 435.0264

Example 641-Chloro-3-[1-[(4-chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]-benzene

Sodium 4-chlorobenzenesulfinate (219 mg, 1.10 mmol) and 3-chlorobenzylbromide (142 μl, 1.03 mmol) were added to dimethoxyethane (5 ml). Theresulting mixture was stirred at 70° C. for 6 hours. After cooling toroom temperature, the solvent was concentrated under reduced pressure.The residue was added with ethyl acetate and from the resulting mixture,the insoluble matter was filtered off. The residue obtained byconcentrating the filtrate under reduced pressure was washed with hexaneto yield a white powder (304 mg).

A toluene (10 ml) solution of the resulting white powder (92 mg), the4-(methylsulfonyl)-1-butanol (96 mg, 0.631 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n-butylphosphorane (148 mg, 0.614 mmol)was heated under reflux for 20 hours under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue was subjected to medium-pressurechromatography on a silica gel column, whereby from the fraction elutedwith hexane:ethyl acetate (=2:3), the title compound (51 mg) wasobtained as a colorless oil.

IR (ATR) ν: 3089, 3023, 1573, 1475, 1394, 1278, 1195, 1139, 1081, 1012,962, 885, 829, 804, 750, 694, 626, 578, 530, 462 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.32-1.50 (2H, m), 1.79-1.97 (2H, m),2.09-2.22 (1H, m), 2.40-2.52 (1H, m), 2.88 (3H, s), 2.90-3.00 (2H, m),3.98 (1H, dd, J=11.2, 3.9 Hz), 6.96 (1H, d, J=7.6 Hz), 7.10 (1H, s),7.20 (1H, t, J=7.6 Hz), 7.28-7.32 (1H, m), 7.35-7.47 (4H, m).

MS (m/z): 435 (M⁺+H).

HRMS (FAB): as C₁₈H₂₁O₄Cl₂S₂ (M⁺+H)

Calculated: 435.0258

Found: 435.0240

Example 651-Chloro-4-[1-[(4-chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene

Sodium 4-chlorobenzenesulfinate (211 mg, 1.06 mmol) and 4-chlorobenzylbromide (218 mg, 1.06 mmol) were added to dimethoxyethane (5 ml),followed by stirring at 70° C. for 6 hours. After cooling to roomtemperature, the solvent was concentrated under reduced pressure. Theresidue was added with ethyl acetate and from the resulting mixture, theinsoluble matter was filtered off. The residue obtained by concentratingthe filtrate under reduced pressure was washed with hexane to yield awhite powder (274 mg).

Then, a toluene (10 ml) solution of the resulting white powder (61 mg),the 4-(methylsulfonyl)-1-butanol (63 mg, 0.414 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (97 mg,0.403 mmol) was heated under reflux for 20 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected tomedium-pressure chromatography on a silica gel column, whereby from thefraction eluted with hexane:ethyl acetate (=2:3), the title compound (37mg) was obtained as a colorless oil.

IR (ATR) ν: 2931, 2871, 1581, 1492, 1475, 1411, 1394, 1276, 1139, 1085,1012, 962, 908, 827, 752, 713, 661, 620, 566, 518, 470 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.35-1.51 (2H, m), 1.75-1.98 (2H, m),2.05-2.25 (1H, m), 2.42-2.55 (1H, m), 2.84-3.10 (2H, m), 2.87 (3H, s),3.99 (1H, dd, J=11.0, 3.9 Hz), 6.99-7.10 (2H, m), 7.20-7.35 (2H, m),7.35-7.55 (4H, m).

MS (m/z): 435 (M⁺+H).

HRMS (FAB) for C₁₈H₂₁O₄Cl₂S₂ (M⁺+H)

Calculated: 435.0258

Found: 435.0240

Example 661-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]naphthalene

Sodium 4-chlorobenzenesulfinate (183 mg, 0.921 mmol) and1-bromomethylnaphthalene (204 mg, 0.921 mmol) were added todimethoxyethane (10 ml). The resulting mixture was stirred at 70° C. for6 hours. After cooling to room temperature, the solvent was concentratedunder reduced pressure. The residue was added with ethyl acetate andfrom the resulting solution, the insoluble matter was filtered off. Theresidue obtained by concentrating the filtrate under reduced pressurewas washed with hexane to yield a white powder (175 mg).

Then, a toluene (10 ml) solution of the resulting white powder (93 mg),the 4-(methylsulfonyl)-1-butanol (92 mg, 0.604 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (142 mg,0.589 mmol) was heated under reflux for 18 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected tomedium-pressure chromatography on a silica gel column, whereby from thefraction eluted with hexane:ethyl acetate (=1:1), the title compound wasobtained as a white solid (80 mg).

IR (ATR) ν: 2929, 2869, 1577, 1511, 1475, 1394, 1301, 1276, 1137, 1083,1012, 962, 906, 863, 808, 763, 709, 640, 622, 574, 532, 457 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.35-1.55 (2H, m), 1.77-1.95 (2H, m),2.29-2.46 (1H, m), 2.62-2.77 (1H, m), 2.80 (3H, s), 2.83-3.00 (2H, m),5.07 (1H, dd, J=10.9, 4.0 Hz), 7.10 (2H, d, J=8.3 Hz), 7.22-7.48 (4H,m), 7.51 (1H, t, J=7.7 Hz), 7.59 (1H, d, J=8.6 Hz), 7.67 (1H, d, J=7.3Hz), 7.78 (1H, d, J=8.1 Hz), 7.83 (1H, d, J=8.3 Hz).

MS (m/z): 451 (M⁺+H).

HRMS (FAB) for C₂₂H₂₄O₄ClS₂ (M⁺+H)

Calculated: 451.0805

Found: 451.0816

Example 672-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]naphthalene

Sodium 4-chlorobenzenesulfinate (211 mg, 1.06 mmol) and2-bromomethylnaphthalene (235 mg, 1.06 mmol) were added todimethoxyethane (5 ml). The resulting mixture was stirred at 70° C. for5 hours. After cooling to room temperature, the solvent was concentratedunder reduced pressure. The residue was added with ethyl acetate andfrom the resulting mixture, the insoluble matter was filtered off. Theresidue obtained by concentrating the filtrate under reduced pressurewas washed with hexane to yield a white powder (90 mg).

Then, a toluene (10 ml) solution of the resulting white powder (60 mg),the 4-(methylsulfonyl)-1-butanol (59 mg, 0.388 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (91 mg,0.379 mmol) was heated under reflux for 21 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected tomedium-pressure chromatography on a silica gel column, whereby from thefraction eluted with hexane:ethyl acetate (=2:3), the title compound wasobtained as a white solid (62 mg).

Melting point: 146.0-147.0° C.

IR (ATR) ν: 2931, 2861, 1581, 1508, 1473, 1457, 1392, 1359, 1309, 1274,1191, 1147, 1126, 1081, 1010, 968, 902, 869, 819, 752, 734, 703, 646,624, 566, 522, 472, 453 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.34-1.51 (2H, m), 1.78-1.99 (2H, m),2.25-2.40 (1H, m), 2.50-2.62 (1H, m), 2.84 (3H, s), 2.89-3.03 (2H, m),4.19 (1H, dd, J=11.2, 3.9 Hz), 7.18-7.36 (4H, m), 7.39-7.61 (4H, m),7.69-7.90 (3H, m).

MS (m/z): 451 (M⁺+H).

Elemental Analysis for C₂₂H₂₃ClO₄S₂

Calculated: C, 58.59%; H, 5.14%; Cl, 7.86%; S, 14.22%.

Found: C, 58.46%; H, 5.03%; Cl, 7.94%; S, 14.33%.

Example 682-Chloro-1-[1-[(4-chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]-4-fluorobenzene

Sodium 4-chlorobenzenesulfinate (197 mg, 0.992 mmol) and2-chloro-4-fluorobenzyl bromide (222 mg, 0.992 mmol) were added todimethoxyethane (5 ml). The resulting mixture was stirred at 70° C. for6 hours. After cooling to room temperature, the solvent was concentratedunder reduced pressure. The residue was added with ethyl acetate andfrom the resulting mixture, the insoluble matter was filtered off. Theresidue obtained by concentrating the filtrate under reduced pressurewas washed with hexane to yield a white powder (225 mg).

Then, a toluene (10 ml) solution of the resulting white powder (61 mg),4-(methylsulfonyl)-1-butanol (59 mg, 0.394 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n-butylphosphorane (93 mg, 0.384 mmol)was heated under reflux for 15 hours under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue was subjected to medium-pressurechromatography on a silica gel column, whereby from the fraction elutedwith hexane:ethyl acetate (=1:1), the title compound was obtained as awhite solid (38 mg).

Melting point: 124.0-125.0° C.

IR (ATR) ν: 2969, 2933, 1604, 1575, 1492, 1475, 1461, 1396, 1315, 1276,1230, 1130, 1085, 1049, 1014, 973, 902, 850, 823, 782, 748, 659, 630,588, 549, 501, 457 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.30-1.50 (2H, m), 1.79-1.98 (2H, m),2.10-2.25 (1H, m), 2.48-2.60 (1H, m), 2.87 (3H, s), 2.95 (2H, t, J=7.7Hz), 4.79 (1H, dd, J=11.1, 4.0 Hz), 6.98 (1H, dd, J=8.3, 2.7 Hz),7.05-7.15 (1H, m), 7.38 (2H, d, J=8.3 Hz), 7.48 (2H, d, J=8.5 Hz),7.60-7.70 (1H, m).

MS (m/z): 453 (M⁺+H).

Elemental Analysis for C₁₈H₁₉C₁₂FO₄S₂

Calculated: C, 47.69%; H, 4.22%; Cl, 15.64%; F, 4.19%; S, 14.55%.

Found: C, 47.44%; H, 4.20%; Cl, 15.37%; F, 4.07%; S, 14.33%.

Example 691,2-Dichloro-4-[1-[(4-chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene

Sodium 4-chlorobenzenesulfinate (208 mg, 1.05 mmol) and3,4-dichlorobenzyl bromide (251 mg, 1.05 mmol) were added todimethoxyethane (5 ml). The resulting mixture was stirred at 70° C. for6 hours. After cooling to room temperature, the solvent was concentratedunder reduced pressure. The residue was added with ethyl acetate andfrom the resulting mixture, the insoluble matter was filtered off. Theresidue obtained by concentrating the filtrate under reduced pressurewas washed with hexane to yield a white powder (270 mg).

Then, a toluene (10 ml) solution of the resulting white powder (66 mg),the 4-(methylsulfonyl)-1-butanol (62 mg, 0.407 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (96 mg,0.397 mmol) was heated under reflux for 15 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected tomedium-pressure chromatography on a silica gel column. From the fractioneluted with hexane:ethyl acetate (=2:3), the title compound was obtainedas a white solid (70 mg).

Melting point: 143.0-144.0° C.

IR (ATR) ν: 2929, 2865, 1573, 1459, 1392, 1365, 1317, 1299, 1276, 1186,1145, 1079, 1031, 1010, 975, 900, 823, 748, 709, 655, 626, 588, 563,518, 474, 439 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.32-1.49 (2H, m), 1.79-1.96 (2H, m),2.05-2.19 (1H, m), 2.39-2.50 (1H, m), 2.88 (3H, s), 2.90-3.00 (2H, m),3.97 (1H, dd, J=11.2, 3.9 Hz), 6.94 (1H, dd, J=8.3, 2.2 Hz), 7.21 (1H,d, J=2.0 Hz), 7.36 (1H, d, J=8.3 Hz), 7.43 (2H, d, J=8.3 Hz), 7.49 (2H,d, J=8.6 Hz).

MS (m/z): 469 (M⁺+H).

Elemental Analysis for C₁₈H₁₉Cl₃O₄S₂

Calculated: C, 46.02%; H, 4.08%; Cl, 22.64%; S, 13.65%.

Found: C, 45.92%; H, 4.06%; Cl, 22.35%; S, 13.59%.

Example 702-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]pyridine

Sodium 4-chlorobenzenesulfinate (200 mg, 1.01 mmol),2-chloromethylpyridine hydrochloride (166 mg, 1.01 mmol) and potassiumacetate (198 mg, 2.02 mmol) were added to n-butanol (5 ml). Theresulting mixture was stirred at 70° C. for 5 hours. After cooling toroom temperature, the solvent was concentrated under reduced pressure.The residue was added with ethyl acetate and from the resulting mixture,the insoluble matter was filtered off. The filtrate was concentratedunder reduced pressure. The residue was subjected to chromatography on asilica gel column. From the fraction eluted with hexane:ethyl acetate(=3:1), a white solid (123 mg) was obtained.

Then, a toluene (10 ml) solution of the resulting solid (49 mg), the4-(methylsulfonyl)-1-butanol (57 mg, 0.374 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n-butylphosphorane (88 mg, 0.366 mmol)was heated under reflux for 2 days under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue was subjected to medium-pressurechromatography on a silica gel column. From the fraction eluted withmethanol:methylene chloride (=1:50), the title compound was obtained asa white solid (40 mg).

Melting point: 140.0-141.0° C.

IR (ATR) ν: 3012, 2948, 1587, 1471, 1436, 1392, 1321, 1290, 1263, 1197,1149, 1089, 1006, 960, 825, 750, 703, 624, 565, 528, 499, 474, 410 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.30-1.52 (2H, m), 1.79-1.99 (2H, m),2.29-2.49 (2H, m), 2.86 (3H, s), 2.93 (2H, t, J=6.8 Hz), 4.33 (1H, dd,J=11.0, 4.2 Hz), 7.20-7.30 (1H, m), 7.32-7.52 (5H, m), 7.67-7.78 (1H,m), 8.40 (1H, d, J=4.9 Hz).

MS (m/z): 402 (M⁺+H).

Elemental Analysis for C₁₇H₂₀NClO₄S₂

Calculated: C, 50.80%; H, 5.02%; N, 3.48%; Cl, 8.82%; S, 15.96%.

Found: C, 50.67%; H, 4.94%; N, 3.53%; Cl, 8.72%; S, 15.90%.

Example 711,4-Dichloro-2-[1-[(4-chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene

Sodium 4-chlorobenzenesulfinate (38 mg, 0.192 mmol) and2,5-dichlorobenzyl bromide (46 mg, 0.192 mmol) were added todimethoxyethane (5 ml). The resulting mixture was stirred at 70° C. for24 hours. After cooling to room temperature, the reaction mixture wassubjected to a short column (silica gel) and the fraction eluted withdiethyl ether was concentrated under reduced pressure. The residue thusobtained was dissolved in toluene (5 ml). To the resulting solution wereadded the 4-(methylsulfonyl)-1-butanol (58 mg, 0.381 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (89 mg,0.370 mmol), followed by heating under reflux for 23 hours under anargon atmosphere. After cooling to room temperature, the reactionmixture was concentrated under reduced pressure. The residue wassubjected to medium-pressure chromatography on a silica gel column. Fromthe fraction eluted with hexane:ethyl acetate (=1:1), the title compound(32 mg, 35%) was obtained as a colorless oil.

IR (ATR) ν: 2933, 2869, 1581, 1465, 1394, 1313, 1278, 1191, 1133, 1083,1039, 1012, 962, 887, 821, 752, 713, 630, 588, 532, 464 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.33-1.50 (2H, m), 1.80-1.96 (2H, m),2.09-2.21 (1H, m), 2.48-2.59 (1H, m), 2.88 (3H, s), 2.90-2.99 (2H, t,J=11.0, 4.2 Hz), 4.79 (1H, dd, J=11.0, 4.2 Hz), 7.15 (1H, d, J=8.6 Hz),7.20-7.29 (1H, m), 7.34-7.40 (2H, m), 7.46-7.52 (2H, m), 7.63 (1H, d,J=2.5 Hz).

MS (m/z): 469, 471 (M⁺+H).

HRMS (FAB) for C₁₈H₂₀O₄Cl₃S₂ (M⁺+H)

Calculated: 468.9869

Found: 468.9907

Example 721-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]-3,5-difluorobenzene

Sodium 4-chlorobenzenesulfinate (49 mg, 0.247 mmol) and3,5-difluorobenzyl bromide (32 μl, 0.247 mmol) were added todimethoxyethane (5 ml). The resulting mixture was stirred at 70° C. for24 hours. After cooling to room temperature, the reaction mixture wassubjected to a short column (silica gel) and the fraction eluted withdiethyl ether was concentrated under reduced pressure. The residue thusobtained was dissolved in toluene (5 ml). To the resulting solution wereadded the 4-(methylsulfonyl)-1-butanol (58 mg, 0.381 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (89 mg,0.370 mmol). The mixture was heated under reflux for 23 hours under anargon atmosphere. After cooling to room temperature, the reactionmixture was concentrated under reduced pressure. The residue wassubjected to medium-pressure chromatography on a silica gel column. Fromthe fraction eluted with hexane:ethyl acetate (=1:1), the title compoundwas obtained as a white solid (39 mg, 36%).

Melting point: 126.0-127.0° C.

IR (ATR) ν: 2940, 1623, 1596, 1463, 1392, 1344, 1319, 1270, 1243, 1203,1145, 1118, 1081, 1010, 987, 952, 863, 823, 752, 707, 680, 624, 539,501, 478, 449 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.35-1.62 (2H, m), 1.78-1.99 (2H, m),2.05-2.19 (1H, m), 2.39-2.51 (1H, m), 2.88 (3H, s), 2.90-3.05 (2H, m),3.98 (1H, dd, J=10.9, 4.0 Hz), 6.62-6.75 (2H, m), 6.75-6.85 (1H, m),7.38-7.58 (4H, m).

MS (m/z): 436 (M⁺+H).

Elemental Analysis for C₁₈H₁₉F₂O₄S₂

Calculated: C, 49.48%; H, 4.38%; Cl, 8.11%; F, 8.70%; S, 14.68%.

Found: C, 49.45%; H, 4.33%; Cl, 8.10%; F, 8.88%; S, 14.69%.

Example 733-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]pyridine

Sodium 4-chlorobenzenesulfinate (207 mg, 1.04 mmol),3-chloromethylpyridine hydrochloride (171 mg, 1.04 mmol) and potassiumacetate (204 mg, 2.08 mmol) were added to n-butanol (5 ml). Theresulting mixture was stirred at 70° C. for 5 hours. After cooling toroom temperature, the solvent was concentrated under reduced pressure.The residue was added with ethyl acetate and from the resulting mixture,the insoluble matter was filtered off. The filtrate was concentratedunder reduced pressure. The residue was subjected to chromatography on asilica gel column and from the fraction eluted with hexane:ethyl acetate(=2:3), a white solid (98 mg) was obtained.

Then, a toluene (10 ml) solution of the resulting solid (29 mg), the4-(methylsulfonyl)-1-butanol (102 mg, 0.670 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (156 mg,0.650 mmol) was heated under reflux for 2 days under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. To the residue was added 1Nhydrochloric acid/ethanol and the mixture was concentrated under reducedpressure. The residue was washed with diethyl ether. The residue wasadded with a saturated aqueous solution of sodium bicarbonate, followedby extraction with ethyl acetate. After the organic layer was dried overanhydrous sodium sulfate, the solvent was concentrated under reducedpressure. The residue was subjected to medium-pressure chromatography ona silica gel column. From the fraction eluted with methanol:methylenechloride (=1:50), the title compound (38 mg) was obtained as a paleyellow oil.

IR (ATR) ν: 2929, 2873, 1575, 1477, 1425, 1394, 1276, 1178, 1132, 1083,1012, 964, 908, 823, 757, 711, 651, 622, 563, 518, 458 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.35-1.52 (2H, m), 1.80-1.99 (2H, m),2.13-2.26 (1H, m), 2.49-2.59 (1H, m), 2.88 (3H, s), 2.90-2.99 (2H, m),4.05 (1H, dd, J=11.1, 4.0 Hz), 7.30 (1H, dd, J=7.8, 4.9 Hz), 7.38-7.48(4H, m), 7.64 (1H, dt, J=8.1, 2.0 Hz), 8.16 (1H, d, J=2.0 Hz), 8.57 (1H,dd, J=4.8, 1.6 Hz).

MS (m/z): 402 (M⁺+H).

HRMS (FAB) for C₁₇H₂₁O₄NClS₂ (M⁺+H)

Calculated: 402.0601

Found: 402.0596

Example 744-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]pyridine

Sodium 4-chlorobenzenesulfinate (207 mg, 1.04 mmol),3-chloromethylpyridine hydrochloride (171 mg, 1.04 mmol) and potassiumacetate (204 mg, 2.08 mmol) were added to n-butanol (5 ml). Theresulting mixture was stirred at 70° C. for 5 hours. After cooling toroom temperature, the solvent was concentrated under reduced pressure.To the residue was added ethyl acetate and from the resulting mixture,the insoluble matter was filtered off. The filtrate was concentratedunder reduced pressure. The residue was subjected to chromatography on asilica gel column and the from the fraction eluted with hexane:ethylacetate (=2:3), a white solid (117 mg) was obtained.

Then, a toluene (10 ml) solution of the resulting solid (52 mg), the4-(methylsulfonyl)-1-butanol (90 mg, 0.592 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n-butylphosphorane (140 mg, 0.582 mmol)was heated under reflux for 2 days under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. To the residue was added 1N hydrochloric acid/ethanol.After concentration under reduced pressure, the residue was washed withdiethyl ether. To the residue was added a saturated aqueous solution ofsodium bicarbonate, followed by extraction with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas concentrated under reduced pressure. The residue was subjected tomedium-pressure chromatography on a silica gel column and from thefraction eluted with methanol:methylene chloride (=1:50), the titlecompound was obtained as a white solid (62 mg).

Melting point: 181.0-182.0° C.

IR (ATR) ν: 2942, 2863, 1590, 1467, 1415, 1311, 1272, 1241, 1201, 1147,1085, 1002, 960, 908, 831, 755, 703, 632, 568, 530, 476, 453 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.30-1.53 (2H, m), 1.76-1.99 (2H, m),2.10-2.25 (1H, m), 2.40-2.57 (1H, m), 2.88 (3H, s), 2.90-3.02 (2H, m),4.00 (1H, dd, J=11.1, 4.0 Hz), 6.95-7.09 (2H, m), 7.32-7.55 (4H, m),8.43-8.60 (2H, m).

MS (m/z): 402 (M⁺+H).

Elemental Analysis for C₁₇H₂₀NClO₄S₂

Calculated: C, 50.80%; H, 5.02%; N, 3.48%; Cl, 8.82%; S, 15.96%.

Found: C, 50.70%; H, 4.93%; N, 3.55%; Cl, 8.10%; S, 15.83%.

Example 752-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]quinoline

Sodium 4-chlorobenzenesulfinate (196 mg, 0.987 mmol),2-chloromethylquinoline hydrochloride (211 mg, 0.987 mmol) and potassiumacetate (194 mg, 1.97 mmol) were added to n-butanol (5 ml). Theresulting mixture was stirred at 70° C. for 5 hours. After cooling toroom temperature, the solvent was concentrated under reduced pressure.To the residue was added ethyl acetate and from the resulting mixture,the insoluble matter was filtered off. The residue obtained byconcentrating the filtrate under reduced pressure was subjected tochromatography on a silica gel column, whereby from the fraction elutedwith hexane:ethyl acetate (=1:1), a white solid (97 mg) was obtained.

Then, a toluene (10 ml) solution of the resulting solid (42 mg), the4-(methylsulfonyl)-1-butanol (104 mg, 0.684 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (160 mg,0.666 mmol) was heated under reflux for 2 days under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected tomedium-pressure chromatography on a silica gel column and from thefraction eluted with hexane:ethyl acetate (=1:3), the title compound (49mg) was obtained as a colorless oil.

IR (ATR) ν: 2931, 2869, 1596, 1581, 1504, 1463, 1428, 1394, 1297, 1278,1133, 1083, 1012, 960, 875, 829, 755, 705, 663, 624, 568, 516, 457 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.30-1.60 (2H, m), 1.79-1.95 (2H, m),2.40-2.50 (2H, m), 2.83 (3H, s), 2.91 (2H, t, J=7.2 Hz), 4.52 (1H, dd,J=9.9, 5.3 Hz), 7.28-7.32 (2H, m), 7.39-7.46 (2H, m), 7.55-7.61 (2H, m),7.67-7.73 (1H, m), 7.77-7.87 (2H, m), 8.19 (1H, d, J=8.6 Hz).

MS (m/z): 452 (M⁺+H).

HRMS (FAB) for C₂₁H₂₃O₄NClS₂ (M⁺+H)

Calculated: 452.0757

Found: 452.0744

Example 764-[1-(4-Chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]-1,2-difluorobenzene

Sodium 4-chlorobenzenesulfinate (45 mg, 0.227 mmol) and3,4-difluorobenzyl bromide (29 μl, 0.227 mmol) were added todimethoxyethane (5 ml). The resulting mixture was stirred at 70° C. for24 hours. After cooling the reaction mixture to room temperature, thesolvent was concentrated under reduced pressure. Ethyl acetate was addedto the residue and from the mixture, the insoluble matter was filteredoff. The filtrate was concentrated under reduced pressure. The residuethus obtained was subjected to chromatography on a silica gel column andthe fraction obtained from the ether eluate was concentrated underreduced pressure. A toluene (5 ml) solution of the residue, the4-(methylsulfonyl)-1-butanol (71 mg, 0.454 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n-butylphosphorane (110 mg, 0.454 mmol)was heated under reflux for 16 hours under an argon atmosphere. Aftercooling to room temperature, the 4-(methylsulfonyl)-1-butanol (71 mg,0.454 mmol) obtained in Referential Example 3 andcyanomethylenetri-n-butylphosphorane (110 mg, 0.454 mmol) were added,followed by heating under reflux for 22 hours under an argon atmosphere.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. The residue was subjected to flashchromatography on a silica gel column and the fraction obtained from thehexane:ethyl acetate (=2:3) eluate was concentrated under reducedpressure, whereby the title compound (12 mg, 12%) was obtained as awhite solid. The solid was washed with hexane-ether and collected byfiltration, whereby the title compound was obtained as a white powder.

Melting point: 122-124° C.

IR (ATR) ν: 2940, 2873, 1610, 1575, 1519, 1467, 1434, 1394, 1317, 1280,1268, 1205, 1145, 1126, 1083, 1012, 962, 877, 819, 765, 754, 707, 632,592, 549, 526, 514, 507, 484, 451, 404 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.32-1.50 (2H, m), 1.79-1.97 (2H, m),2.03-2.18 (1H, m), 2.40-2.50 (1H, m), 2.88 (3H, s), 2.90-3.00 (2H, m),3.98 (1H, dd, J=11.0, 3.9 Hz), 6.77-6.81 (1H, m), 6.99-7.10 (2H, m),7.38-7.53 (4H, m).

MS (m/z): 437 (M⁺+H).

HRMS (FAB) for C₁₈H₂₀O₄ClF₂S₂ (M⁺+H)

Calculated: 437.0460

Found: 437.0494

Example 771-[1-(4-Chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]-2,3-difluorobenzene

To dimethoxyethane (5 ml) were added sodium 4-chlorobenzenesulfinate (45mg, 0.227 mmol) and 2,3-difluorobenzyl bromide (29 μl, 0.227 mmol). Theresulting mixture was stirred at 70° C. for 24 hours. After cooling atroom temperature, the solvent was concentrated under reduced pressure.Ethyl acetate was added to the residue and from the mixture, theinsoluble matter was filtered off. The filtrate was concentrated underreduced pressure. The residue was subjected to chromatography on asilica gel column. The fraction obtained from the ether eluate wasconcentrated under reduced pressure. A toluene (10 ml) solution of theresidue, the 4-(methylsulfonyl)-1-butanol (71 mg, 0.454 mmol) obtainedin Referential Example 3 and cyanomethylenetri-n-butylphosphorane (110mg, 0.454 mmol) was heated under reflux for 15 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column. The fraction obtained from the55% ethyl acetate/hexane eluate was concentrated under reduced pressureto give the title compound (37 mg, 37%) as a white solid. The solid waswashed with hexane-ether and filtered, whereby the title compound wasobtained as a white powder.

Melting point: 141-143° C.

IR (ATR) ν: 2948, 2867, 1625, 1575, 1484, 1396, 1317, 1272, 1230, 1199,1149, 1124, 1085, 1012, 966, 935, 894, 808, 761, 717, 659, 628, 584,547, 518, 472, 443 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.37-1.60 (2H, m), 1.81-1.96 (2H, m),2.11-2.25 (1H, m), 2.45-2.57 (1H, m), 2.88 (3H, s), 2.96 (2H, t, J=7.9Hz), 4.53 (1H, dd, J=11.1, 4.0 Hz), 7.10-7.19 (2H, m), 7.22-7.33 (1H,m), 7.39-7.44 (2H, m), 7.49-7.54 (2H, m).

MS (m/z): 437 (M⁺+H).

Element Analysis for C₁₈H₁₉ClF₂O₄S₂

Calculated: C, 49.48%; H, 4.38%; Cl, 8.11%; F, 8.70%; S, 14.68%.

Found: C, 49.38%; H, 4.34%; Cl, 8.13%; F, 8.60%; S, 14.56%.

Example 781-Chloro-3-[1-(4-chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]-2-fluorobenzene

To dimethoxyethane (5 ml) were added sodium 4-chlorobenzenesulfinate (45mg, 0.227 mmol) and 3-chloro-2-fluorobenzyl bromide (51 mg, 0.227 mmol).The resulting mixture was stirred at 70° C. for 24 hours. After coolingthe reaction mixture to room temperature, the solvent was concentratedunder reduced pressure. Ethyl acetate was added to the residue and fromthe resulting mixture, the insoluble matter was filtered off. Thefiltrate was concentrated under reduced pressure. The residue wassubjected to chromatography on a silica gel column and the fractionobtained from the ether eluate was concentrated under reduced pressure.A toluene (5 ml) solution of the resulting residue, the4-(methylsulfonyl)-1-butanol (71 mg, 0.454 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n-butylphosphorane (110 mg, 0.454 mmol)was heated under reflux for 5 days under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was added with the4-(methylsulfonyl)-1-butanol (71 mg, 0.454 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n-butylphosphorane (110 mg, 0.454 mmol),followed by heating under reflux for 12.5 hours under an argonatmosphere. The reaction mixture was cooled to room temperature andthen, concentrated under reduced pressure. The residue was subjected toflash chromatography on a silica gel column, and the fraction obtainedfrom the hexane:ethyl acetate (=1:1) eluate was concentrated underreduced pressure to give the title compound (42 mg, 41%) as a whitesolid. The resulting solid was washed with hexane-ether and collected byfiltration, whereby the title compound was obtained as a white powder.

Melting point: 131-132° C.

IR (ATR) ν: 3038, 2938, 1579, 1459, 1392, 1313, 1286, 1234, 1151, 1120,1085, 1010, 966, 914, 811, 750, 719, 671, 620, 584, 522, 458 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.33-1.60 (2H, m), 1.80-1.98 (2H, m),2.11-2.25 (1H, m), 2.42-2.56 (1H, m), 2.88 (3H, s), 2.96 (2H, t, J=7.9Hz), 4.53 (1H, dd, J=11.1, 4.3 Hz), 7.11-7.20 (1H, m), 7.33-7.46 (4H,m), 7.46-7.56 (2H, m).

MS (m/z): 453 (M⁺+H).

Elemental Analysis for C₁₈H₁₉Cl₂FO₄S₂

Calculated: C, 47.69%; H, 4.22%; Cl, 15.64%; F, 4.19%; S, 14.15%.

Found: C, 47.40%; H, 4.18%; Cl, 15.42%; F, 4.16%; S, 14.08%.

Example 794-Chloro-2-[1-(4-chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]-1-fluorobenzene

To dimethoxyethane (5 ml) were added sodium 4-chlorobenzenesulfinate (45mg, 0.227 mmol) and 2-bromomethyl-4-chloro-1-fluorobenzene (51 mg, 0.227mmol). The resulting mixture was stirred at 70° C. for 24 hours. Aftercooling the reaction mixture to room temperature, the solvent wasconcentrated under reduced pressure. Ethyl acetate was added to theresidue and from the resulting mixture, the insoluble matter wasfiltered off. The filtrate was concentrated under reduced pressure. Theresidue was subjected to chromatography on a silica gel column, and thefraction obtained from the ether eluate was concentrated under reducedpressure. A toluene (5 ml) solution of the residue thus obtained, the4-(methylsulfonyl)-1-butanol (71 mg, 0.454 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n-butylphosphorane (110 mg, 0.454 mmol)was heated under reflux for 16 hours under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was added with4-(methylsulfonyl)-1-butanol (71 mg, 0.454 mmol) andcyanomethylenetri-n-butylphosphorane (110 mg, 0.454 mmol), followed byheating under reflux for 22 hours under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue was subjected to flash chromatography on asilica gel column and the fraction obtained from the hexane:ethylacetate eluate (=1:1) was concentrated under reduced pressure to givethe title compound (53 mg, 51%) as a white solid. The resulting solidwas washed with hexane-ether and then collected by filtration, wherebythe title compound was obtained as a white powder.

Melting point: 116-117° C.

IR (ATR) ν: 3097, 2946, 1577, 1490, 1407, 1317, 1278, 1240, 1174, 1147,1083, 1047, 1012, 956, 916, 881, 823, 754, 711, 649, 626, 566, 538, 474,433 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.38-1.52 (2H, m), 1.81-1.99 (2H, m),2.09-2.21 (1H, m), 2.45-2.57 (1H, m), 2.89 (3H, s), 2.91-3.02 (2H, m),4.48-4.53 (1H, m), 6.8.3 (1H, t, J=8.9 Hz), 7.23-7.30 (1H, m), 7.38-7.45(2H, m), 7.46-7.59 (3H, m).

MS (m/z): 453 (M⁺+H).

Elemental Analysis for C₁₈H₁₉Cl₂FO₄S₂

Calculated: C, 47.69%; H, 4.22%; Cl, 15.64%; F, 4.19%; S, 14.15%.

Found: C, 47.52%; H, 4.19%; Cl, 15.47%; F, 4.24%; S, 14.08%.

Referential Example 7 1-Iodo-4-(methylsulfonyl)butane

Iodine (1.87 g, 7.35 mmol) was added to a methylene chloride (30 ml)solution of the 4-(methylsulfonyl)-1-butanol (746 mg, 4.90 mmol)obtained in Referential Example 3, imidazole (500 mg, 7.35 mmol) andtriphenylphosphine (1.93 g, 7.35 mmol) and the resulting mixture wasstirred for 3 hours at room temperature. The reaction mixture was addedwith a saturated aqueous solution of sodium thiosulfate. The resultingmixture was extracted with methylene chloride. The extract was driedover anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected tochromatography on a silica gel column. The fraction obtained from themethanol:methylene chloride (=1:100) eluate was concentrated underreduced pressure, whereby the title compound (1.18 g, 92%) was obtainedas a pale yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.92-2.08 (4H, m), 2.93 (3H, s), 3.00-3.10(2H, m), 3.18-3.28 (2H, m).

MS (m/z): 263 (M⁺+H).

Example 80 2-(4-Chlorophenylsulfonylmethyl)-1,3-difluorobenzene

To dimethoxyethane (10 ml) were added sodium 4-chlorobenzenesulfinate(205 mg, 1.03 mmol) and 2,6-difluorobenzyl bromide (214 mg, 1.03 mmol).The resulting mixture was stirred at 70° C. for 18 hours. After coolingthe reaction mixture to room temperature, the solvent was concentratedunder reduced pressure. Ethyl acetate was added to the residue and fromthe resulting mixture, the insoluble matter was filtered off. Thefiltrate was concentrated under reduced pressure. The residue wassubjected to chromatography on a silica gel column and the fractionobtained from the ether eluate was concentrated under reduced pressure.The residue was subjected to chromatography on a silica gel column. Thefraction obtained from the hexane:ethyl acetate (=10:1) eluate wasconcentrated under reduced pressure, whereby the title compound (289 mg,93%) was obtained as a white solid.

IR (ATR) ν: 3097, 2989, 1625, 1575, 1509, 1473, 1407, 1392, 1319, 1272,1245, 1197, 1182, 1132, 1083, 998, 889, 854, 831, 802, 777, 742, 719,686, 626, 566, 512, 478, 449, 418 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 4.48 (2H, s), 6.88 (2H, t, J=7.9 Hz),7.29-7.39 (1H, m), 7.47 (2H, d, J=8.6 Hz), 7.68 (2H, d, J=8.6 Hz).

MS (m/z): 303 (M⁺+H).

Example 812-[1-(4-Chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]-1,3-difluorobenzene

At −78° C., butyl lithium (a 1.57M hexane solution; 0.55 ml, 0.864 mmol)was added dropwise to a dimethoxyethane (10 ml) solution of2-(4-chlorophenylsulfonylmethyl)-1,3-difluorobenzene (218 mg, 0.720mmol). After stirring at −78° C. for 30 minutes, a dimethoxyethane (5ml) solution of the 1-iodo-4-(methylsulfonyl)butane (226 mg, 0.864 mmol)obtained in Referential Example 7 was added dropwise. The temperature ofthe reaction mixture was elevated gradually to room temperature and atroom temperature, the mixture was stirred for 15 hours. Water was addedto the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated underreduced pressure. The residue thus obtained was subjected to flashchromatography on a silica gel column and the fraction obtained from the55% ethyl acetate/hexane eluate was concentrated under reduced pressureto give the title compound (53 mg, 17%) as a white solid. The resultingsolid was washed with hexane and collected by filtration, whereby thetitle compound was obtained as a white powder.

Melting point: 118-119° C.

IR (ATR) ν: 2946, 1621, 1585, 1471, 1459, 1396, 1355, 1322, 1301, 1274,1226, 1151, 1132, 1087, 1012, 989, 958, 925, 829, 773, 761, 752, 717,624, 572, 522, 485, 458, 406 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.35-1.55 (2H, m), 1.81-1.95 (2H, m),2.48-2.58 (2H, m), 2.88 (3H, s), 2.91-3.10 (2H, m), 2.97 (1H, dd,J=15.8, 6.7 Hz), 6.75-7.00 (2H, m), 7.25-7.35 (1H, m), 7.42 (2H, d,J=8.6 Hz), 8.30 (2H, d, J=8.3 Hz).

MS (m/z): 437 (M⁺+H).

Elemental Analysis for C₁₈H₁₉ClF₂O₄S₂

Calculated: C, 49.48%; H, 4.38%; Cl, 8.11%; F, 8.70%; S, 14.68%.

Found: C, 49.25%; H, 4.32%; Cl, 8.02%; F, 8.50%; S, 14.70%.

Example 82 1-(4-Chlorophenylsulfonylmethyl)-3-methoxybenzene

A dimethoxyethane (10 ml) suspension of sodium 4-chlorobenzenesulfinate(210 mg, 1.06 mmol) and 3-methoxybenzyl chloride (154 μl, 1.06 mmol) wasstirred at 70° C. for 16 hours. After cooling to room temperature,butanol (2 ml) and tetrabutylammonium bromide (45 mg) were added and theresulting mixture was stirred further at 70° C. for 16 hours. Aftercooling the reaction mixture to room temperature, the solvent wasconcentrated under reduced pressure. Ethyl acetate was added to theresidue. The mixture was washed successively with water and brine, anddried over anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate (=5:1) eluate was concentrated under reducedpressure, whereby the title compound (216 mg, 69%) was obtained as awhite solid.

IR (ATR) ν: 3064, 2979, 2842, 1598, 1488, 1469, 1434, 1392, 1313, 1268,1176, 1130, 1085, 1033, 1012, 941, 879, 823, 792, 765, 742, 692, 620,574, 528, 455 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 3.74 (3H, s), 4.27 (2H, s), 6.59-6.68 (2H,m), 6.82-6.90 (1H, m), 7.17 (1H, t, J=7.8 Hz), 7.42 (2H, d, J=8.6 Hz),7.56 (2H, d, J=8.6 Hz).

MS (m/z): 297 (M⁺+H).

Example 831-[1-(4-Chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]-3-methoxybenzene

A toluene (10 ml) solution of1-(4-chlorophenylsulfonylmethyl)-3-methoxybenzene (80 mg, 0.269 mmol),the 4-(methylsulfonyl)-1-butanol (62 mg, 0.404 mmol) obtained inReferential Example 3, and cyanomethylenetri-n-butylphosphorane (98 mg,0.404 mmol) was heated under reflux for 3 days under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate (=1:1) eluate wasconcentrated under reduced pressure to give the title compound (61 mg,52%) as a white solid. The white solid was washed with hexane, andcollected by filtration, whereby the title compound was obtained as awhite powder.

Melting point: 91-93° C.

IR (ATR) ν: 2967, 2929, 1594, 1494, 1469, 1455, 1394, 1315, 1272, 1255,1222, 1189, 1145, 1132, 1085, 1037, 1012, 970, 879, 850, 804, 759, 705,688, 632, 603, 532, 493, 464 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.37-1.50 (2H, m), 1.79-1.93 (2H, m),2.10-2.23 (1H, m), 2.40-2.52 (1H, m), 2.86 (3H, s), 2.89-2.98 (2H, m),3.73 (3H, s), 3.97 (1H, dd, J=11.1, 3.8 Hz), 6.59-6.67 (2H, m),6.80-6.89 (1H, m), 7.15 (1H, d, J=8.0 Hz), 7.35 (2H, d, J=8.6 Hz), 7.44(2H, d, J=8.6 Hz).

MS (m/z): 431 (M⁺+H).

Elemental Analysis for C₁₉H₂₃ClO₅S₂

Calculated: C, 52.95%; H, 5.38%; Cl, 8.23%; S, 14.88%.

Found: C, 52.89%; H, 5.25%; Cl, 8.33%; S, 14.87%.

Example 84 1-(4-Chlorophenylsulfonylmethyl)-4-methoxybenzene

A butanol (5 ml) suspension of sodium 4-chlorobenzenesulfinate (264 mg,1.33 mmol), 4-methoxybenzyl chloride (181 μl, 1.33 mmol) andtetrabutylammonium bromide (24 mg) was stirred at 70° C. for 3 days.After cooling the reaction mixture to room temperature, the solvent wasconcentrated under reduced pressure. Ethyl acetate was added to theresidue and the mixture was washed successively with water and brine,and then dried over anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The residue wassubjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate (=5:1) eluate wasconcentrated under reduced pressure, whereby the title compound (90 mg,23%) was obtained as a white solid.

IR (ATR) ν: 3072, 2996, 2942, 2836, 1608, 1583, 1509, 1467, 1396, 1309,1292, 1240, 1176, 1147, 1089, 1031, 1016, 977, 956, 887, 829, 767, 715,630, 532, 474, 431 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 3.80 (3H, s), 4.25 (2H, s), 6.80 (2H, d,J=8.8 Hz), 7.00 (2H, d, J=8.6 Hz), 7.42 (2H, d, J=8.3 Hz), 7.54 (2H, d,J=8.6 Hz).

Example 851-[1-(4-Chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]-4-methoxybenzene

A toluene (10 ml) solution of1-(4-chlorophenylsulfonylmethyl)-4-methoxybenzene (72 mg, 0.243 mmol),the 4-(methylsulfonyl)-1-butanol (70 mg, 0.460 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (111 mg,0.460 mmol) was heated under reflux for 15 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasadded with the 4-(methylsulfonyl)-1-butanol (70 mg, 0.460 mmol) obtainedin Referential Example 3 and cyanomethylenetri-n-butylphosphorane (111mg, 0.460 mmol) and the mixture was heated under reflux for 22 hoursunder an argon atmosphere. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. The residuethus obtained was subjected to flash chromatography on a silica gelcolumn, and the fraction obtained from the hexane:ethyl acetate (=1:1)eluate was concentrated under reduced pressure to give the titlecompound (33 mg, 32%) as a white solid. The resulting white solid waswashed with hexane and then collected by filtration, whereby the titlecompound was obtained as a white powder.

Melting point: 136-138° C.

IR (ATR) ν: 3012, 2937, 1608, 1583, 1511, 1471, 1392, 1319, 1292, 1268,1253, 1178, 1145, 1130, 1085, 1029, 1012, 964, 833, 823, 771, 754, 723,628, 574, 551, 530, 497, 472, 439 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.37-1.50 (2H, m), 1.79-1.93 (2H, m),2.10-2.23 (1H, m), 2.40-2.52 (1H, m), 2.86 (3H, s), 2.89-2.98 (2H, m),3.73 (3H, s), 3.97 (1H, dd, J=11.1, 3.8 Hz), 6.59-6.67 (2H, m),6.80-6.89 (1H, m), 7.15 (1H, d, J=8.0 Hz), 7.35 (2H, d, J=8.6 Hz), 7.44(2H, d, J=8.6 Hz).

MS (m/z): 431 (M⁺+H).

Elemental Analysis for C₁₉H₂₃ClO₂S₂

Calculated: C, 52.95%; H, 5.38%; Cl, 8.23%; S, 14.88%.

Found: C, 52.99%; H, 5.29%; Cl, 8.29%; S, 14.82%.

Referential Example 8 Methyl 3-(N,N-dimethylcarbamoyl)benzoate

To a methylene chloride (20 ml) solution of monomethyl isophthalate (317mg, 1.76 mmol) were added dimethylamine hydrochloride (172 mg, 2.11mmol), 1-hydroxybenzotriazole (287 mg, 1.76 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (404 mg,2.11 mmol) and N-methylmorpholine (0.23 ml, 2.11 mmol) and the resultingmixture was stirred at room temperature for 21 hours. The reactionmixture was concentrated under reduced pressure. Ethyl acetate was addedto the residue. The resulting mixture was washed successively with 1Nhydrochloric acid, a saturated aqueous solution of sodium bicarbonate,and brine, and dried over anhydrous sodium sulfate. After filtration,the filtrate was concentrated under reduced pressure. The residue wassubjected to chromatography on a silica gel column and the fractionobtained from the methanol:methylene chloride (=1:50) eluate wasconcentrated under reduced pressure, whereby the title compound (290 mg,80%) was obtained as a colorless oil.

IR (ATR) ν: 1720, 1633, 1583, 1500, 1436, 1392, 1286, 1255, 1205, 1112,1076, 979, 933, 823, 773, 730, 696, 669, 638, 580, 489, 439 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 2.99 (3H, s), 3.13 (3H, s), 3.93 (3H, s),7.49 (1H, t, J=8.2 Hz), 7.63 (1H, t, J=7.6 Hz), 8.05-8.15 (2H, m).

MS (m/z): 208 (M⁺+H).

Referential Example 9 3-Hydroxymethyl-N,N-dimethylbenzamide

Under ice cooling, sodium borohydride (264 mg, 6.97 mmol) was added toan ethanol (15 ml) solution of methyl 3-(N,N-dimethylcarbamoyl)benzoate(289 mg, 1.39 mmol). The temperature of the resulting mixture wasallowed to rise back to room temperature and then, stirring wasconducted at 50° C. for 14 hours. After the reaction mixture was cooledback to room temperature, it was ice cooled. Sodium borohydride (264 mg,6.97 mmol) was added and the mixture was stirred at 50° C. for 6 hours.The reaction mixture was ice cooled, and then added with water, followedby concentration under reduced pressure. The residue thus obtained wasadded with water, followed by extraction with methylene chloride. Theextract was dried over anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The residue wassubjected to chromatography on a silica gel column, and the fractionobtained from the methanol:methylene chloride (=1:30) eluate wasconcentrated under reduced pressure, whereby the title compound (196 mg,79%) was obtained as a colorless oil.

IR (ATR) ν: 3367, 2929, 2869, 1600, 1583, 1508, 1479, 1452, 1394, 1267,1236, 1170, 1097, 1079, 1049, 898, 800, 746, 719, 694, 642, 431 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 2.46 (1H, br s), 2.97 (3H, s), 3.11 (3H, s),4.67 (2H, br d, J=2.9 Hz), 7.23-7.48 (4H, m).

MS (m/z): 180 (M⁺+H).

Example 86 3-(4-Chlorophenylsulfonylmethyl)-N,N-dimethylbenzamide

To a methylene chloride (15 ml) solution of3-hydroxymethyl-N,N-dimethylbenzamide (184 mg, 1.03 mmol) were addedcarbon tetrabromide (511 mg, 1.59 mmol) and triphenylphosphine (404 mg,1.54 mmol). The resulting mixture was stirred at room temperature for4.5 hours. The reaction mixture was concentrated under reduced pressure.The residue thus obtained was subjected to flash column chromatographyand the fraction obtained from the hexane:ethyl acetate (=1:1) eluatewas concentrated under reduced pressure to give a colorless oil (239mg).

A dimethoxyethane (15 ml) suspension of the resulting colorless oil (239mg, 0.987 mmol) and sodium 4-chlorobenzenesulfinate (234 mg, 1.18 mmol)was stirred at 70° C. for 3 days. After cooling the reaction mixture toroom temperature, the solvent was concentrated under reduced pressure.Ethyl acetate was added to the residue, followed by successive washingwith water and brine and drying over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was subjected to flash chromatography on a silica gel column andthe fraction obtained from the 70% ethyl acetate/hexane eluate wasconcentrated under reduced pressure, whereby the title compound (125 mg,37%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 2.89 (3H, s), 3.09 (3H, s), 4.32 (2H, s),7.10-7.50 (6H, m), 7.59 (2H, d, J=8.6 Hz).

MS (m/z): 338 (M⁺+H).

Example 873-[1-(4-Chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]-N,N-dimethylbenzamide

A toluene (10 ml) solution of3-(4-chlorophenylsulfonylmethyl)-N,N-dimethylbenzamide (69 mg, 0.204mmol), the 4-(methylsulfonyl)-1-butanol (62 mg, 0.409 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (99 mg,0.409 mol) was heated under reflux for 15 hours under an argonatmosphere. After cooling to room temperature, the4-(methylsulfonyl)-1-butanol (62 mg, 0.504 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n-butylphosphorane (99 mg, 0.504 mmol)were added. The reaction mixture was heated under reflux for 23 hoursunder an argon atmosphere. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. The residuewas subjected to flash chromatography on a silica gel column, and thefraction obtained from the methanol:methylene chloride (=1:50) eluatewas concentrated under reduced pressure, whereby the title compound (37mg, 38%) was obtained as an amorphous substance.

IR (ATR) ν: 2927, 1625, 1581, 1504, 1475, 1394, 1276, 1172, 1141, 1083,1012, 964, 908, 819, 754, 705, 626, 551, 516, 468 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.32-1.49 (2H, m), 1.78-1.92 (2H, m),2.12-2.28 (1H, m), 2.40-2.50 (1H, m), 2.83 (3H, br s), 2.87 (3H, s),2.90-2.98 (2H, m), 3.08 (3H, br s), 4.05 (1H, dd, J=11.1, 3.8 Hz), 7.12(1H, br s), 7.19-7.25 (1H, m), 7.32-7.40 (4H, m), 7.48 (2H, d, J=8.6Hz).

MS (m/z): 472 (M⁺+H)

HRMS (FAB) for C₂₁H₂₇O₅NClS₂ (M⁺+H)

Calculated: 472.1019

Found: 472.1010

Example 88 2-(4-Chlorophenylsulfonylmethyl)-N,N-dimethylbenzamide

To a methanol (5 ml) solution of phthalide (639 mg, 4.76 mmol) was addeda 50% aqueous solution (2 ml) of dimethylamine and the mixture wasstirred at 70° C. for 14 hours. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. To the residuewas added methylene chloride. The mixture was dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated underreduced pressure. The residue was subjected to chromatography on asilica gel column and the fraction obtained from the methanol:methylenechloride (=1:40) eluate was concentrated under reduced pressure to yielda colorless oil (248 mg, 29%). To a methylene chloride (10 ml) solutionof the colorless oil (238 mg, 1.33 mmol) were added triphenylphosphine(522 mg, 1.99 mmol) and carbon tetrabromide (660 mg, 1.99 mmol) and themixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated under reduced pressure. The residue wassubjected to chromatography on a silica gel column and the fractionobtained from the hexane:ethyl acetate (=3:2) eluate was concentratedunder reduced pressure. The residue was dissolved in butanol (10 ml),followed by the addition thereto sodium 4-chlorobenzenesulfinate (264mg, 1.33 mmol). The mixture was stirred at 70° C. for 2 days. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. Ethyl acetate was added to the residue, followed bysuccessive washing with water and brine and drying over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure. The residue was subjected to flash chromatography on a silicagel column, and the fraction obtained from the hexane:ethyl acetate(=3:2) eluate was concentrated under reduced pressure, whereby the titlecompound (216 mg, 48%) was obtained as an amorphous substance.

¹H-NMR (400 MHz, CDCl₃) δ: 2.97 (3H, s), 3.13 (3H, s), 7.50 (2H, d,J=8.8 Hz), 7.73 (2H, d, J=8.6 Hz).

IR (ATR) ν: 2931, 1621, 1598, 1581, 1504, 1475, 1444, 1392, 1317, 1278,1191, 1151, 1083, 1068, 1012, 879, 827, 777, 757, 740, 705, 636, 607,566, 536, 466, 447 cm⁻¹.

MS (m/z): 338 (M⁺+H).

Example 892-[1-(4-Chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]-N,N-dimethylbenzamide

A toluene (5 ml) solution of2-(4-chlorophenylsulfonylmethyl)-N,N-dimethylbenzamide (161 mg, 0.477mmol), the 4-(methylsulfonyl)butanol (100 mg, 0.657 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (159 mg,0.657 mmol) was heated under reflux for 17 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasadded with the 4-(methylsulfonyl)butanol (100 mg, 0.657 mmol) obtainedin Referential Example 3 and cyanomethylenetri-n-butylphosphorane (159mg, 0.657 mmol). The mixture was stirred under an argon atmosphere for24 hours. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe 80% ethyl acetate/hexane eluate was concentrated under reducedpressure, whereby the title compound (79 mg, 35%) was obtained as anamorphous substance.

¹H-NMR (400 MHz, CDCl₃) δ: 1.25-1.49 (2H, m), 1.63-1.80 (1H, m),1.80-1.93 (1H, m), 2.00-2.20 (2H, m), 2.76-2.95 (2H, m), 2.82 (3H, s),2.84 (3H, s), 3.11 (3H, s), 4.70-4.82 (1H, m), 7.22 (1H, d, J=7.3 Hz),7.32-7.46 (3H, m), 7.49 (2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz).

IR (ATR) ν: 2931, 2873, 1621, 1581, 1506, 1475, 1448, 1394, 1278, 1222,1182, 1137, 1083, 1012, 962, 823, 755, 707, 630, 561, 518, 460 cm⁻¹.

MS: 472 (M⁺+H).

HRMS (FAB) for C₂₁H₂₇O₅NClS₂ (M⁺+H)

Calculated: 472.1019

Found: 472.1023

Example 90 3-(4-Chlorophenylsulfonylmethyl)benzonitrile

A dimethoxyethane (15 ml) suspension of sodium 4-chlorobenzenesulfinate(270 mg, 1.36 mmol) and 3-bromomethylbenzonitrile (222 mg, 1.13 mmol)was stirred at 70° C. for 3 days. After cooling the reaction mixture toroom temperature, the solvent was concentrated under reduced pressure.Ethyl acetate was added to the residue. The mixture was washedsuccessively with water and brine and then, dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure. The residue was subjected to flash chromatography on a silicagel column and the fraction obtained from the hexane:ethyl acetate(=3:1) eluate was concentrated under reduced pressure, whereby the titlecompound (318 mg, 96%) was obtained as a white solid.

IR (ATR) ν: 3087, 2985, 2229, 1581, 1581, 1475, 1432, 1394, 1317, 1282,1265, 1228, 1145, 1081, 1012, 929, 904, 885, 844, 811, 798, 763, 723,686, 651, 626, 578, 545, 522, 484, 462 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 4.32 (2H, s), 7.38-7.52 (5H, m), 7.60 (2H, d,J=8.8 Hz), 7.66 (1H, d, J=7.6 Hz).

MS (m/z): 292 (M⁺+H).

Example 913-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzonitrile

A toluene (10 ml) solution of3-(4-chlorophenylsulfonylmethyl)benzonitrile (60 mg, 0.204 mmol), the4-(methylsulfonyl)-1-butanol (62 mg, 0.409 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n butylphosphorane (99 mg, 0.409 mmol)was heated under reflux for 15 hours under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was added with the4-(methylsulfonyl)-1-butanol (62 mg, 0.504 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n-butylphosphorane (99 mg, 0.504 mmol),followed by heating under reflux for 23 hours under an argon atmosphere.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. The residue was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate (=1:2) eluate was concentrated under reducedpressure, whereby the title compound (69 mg, 79%) was obtained as anamorphous substance.

IR (ATR) ν: 2931, 2229, 1579, 1475, 1432, 1394, 1278, 1137, 1083, 1051,1012, 964, 914, 813, 752, 688, 649, 613, 549, 516, 466 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.30-1.50 (2H, m), 1.79-1.97 (2H, m),2.10-2.22 (1H, m), 2.40-2.51 (1H, m), 2.89 (3H, s), 2.90-3.00 (2H, m),4.06 (1H, dd, J=11.1, 4.0 Hz), 7.35-7.50 (7H, m), 7.64 (1H, d, J=7.3Hz).

MS (m/z): 426 (M⁺+H).

Elemental Analysis for C₁₉H₂₀ClNO₄S₂.0.25H₂O

Calculated: C, 53.02%; H, 4.80%; Cl, 8.24%; N, 3.25%; S, 14.90%.

Found: C, 52.94%; H, 4.85%; Cl, 8.54%; N, 3.25%; S, 14.93%.

Example 92 2-(4-Chlorophenylsulfonylmethyl)benzonitrile

A dimethoxyethane (5 ml) suspension of sodium 4-chlorobenzenesulfinate(218 mg, 1.10 mmol) and 2-bromomethylbenzonitrile (215 mg, 1.10 mmol)was stirred at 70° C. for 17 hours. After cooling the reaction mixtureto room temperature, the solvent was concentrated under reducedpressure. The residue thus obtained was subjected to chromatography on ashort silica gel column and the fraction obtained from the ether eluatewas concentrated under reduced pressure. The residue was subjected tochromatography on a silica gel column and the fraction obtained from thehexane:ethyl acetate (=3:1) eluate was concentrated under reducedpressure to give a white solid. The resulting white solid was washedwith ether, and collected by filtration, whereby the title compound (226mg, 70%) was obtained as a white powder.

IR (ATR) ν: 3079, 2979, 2227, 1573, 1488, 1473, 1450, 1425, 1392, 1321,1299, 1280, 1253, 1209, 1174, 1143, 1081, 1010, 946, 904, 879, 829, 781,759, 711, 682, 632, 593, 532, 480, 451 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 4.58 (2H, s), 7.43-7.51 (3H, m), 7.56-7.68(5H, m).

Example 932-[1-[(4-chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzonitrile

A toluene (5 ml) solution of2-(4-chlorophenylsulfonylmethyl)benzonitrile (96 mg, 0.329 mmol), the4-(methylsulfonyl)-1-butanol (100 mg, 0.657 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (159 mg,0.657 mol) was heated under reflux for 22 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe 60% ethyl acetate/hexane eluate was concentrated under reducedpressure, whereby the title compound (139 mg, 99%) was obtained as anamorphous substance.

IR (ATR) ν: 3089, 2931, 2225, 1575, 1475, 1448, 1394, 1315, 1295, 1278,1214, 1176, 1139, 1124, 1083, 1012, 962, 908, 827, 794, 754, 711, 628,553, 516, 470 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.30-1.54 (2H, m), 1.81-1.98 (2H, m),2.20-2.31 (1H, m), 2.47-2.59 (1H, m), 2.88 (3H, s), 2.90-3.00 (2H, m),4.63 (1H, dd, J=11.0, 4.2 Hz), 7.38-7.60 (6H, m), 7.67-7.73 (1H, m),7.79 (1H, d, J=8.1 Hz).

MS (m/z): 426 (M⁺+H).

HRMS (FAB) for C₁₉H₂₁O₄NClS₂ (M⁺+H)

Calculated: 426.0601

Found: 426.0636

Example 94 1-Chloro-4-(cyclohexylmethylsulfonyl)benzene

To an acetonitrile (10 ml) solution of 4-chlorobenzenethiol (230 mg,1.59 mmol and cyclohexylmethyl bromide (222 μl, 1.59 mmol) was addedpotassium carbonate (329 mg, 2.38 mmol) and the mixture was stirred atroom temperature for 3 hours. The reaction mixture was concentratedunder reduced pressure. To the residue was added hexane and theinsoluble matter was filtered off. The filtrate was concentrated underreduced pressure. The residue thus obtained was dissolved in methylenechloride (20 ml), followed by the addition of 3-chloroperbenzoic acid(576 mg, 3.34 mmol). The mixture was stirred at room temperature for17.5 hours. The reaction mixture was concentrated under reducedpressure. Ethyl acetate was added and the mixture was washedsuccessively with a saturated aqueous solution of sodium bicarbonate andbrine and dried over anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The residue wasdissolved in methylene chloride. To the resulting solution was added a1N aqueous solution of sodium hydroxide to separate the organic layer.The organic layer was dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was subjected to chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate (=15:1) eluate wasconcentrated under reduced pressure, whereby the title compound (301 mg,69%) was obtained as a white solid.

IR (ATR) ν: 2921, 2850, 1583, 1475, 1446, 1394, 1305, 1274, 1172, 1143,1083, 1014, 964, 892, 846, 831, 782, 761, 744, 703, 669, 632, 559, 528,478, 426 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.00-1.35 (5H, m), 1.60-1.76 (3H, m),1.80-2.08 (3H, m), 2.97 (2H, d, J=6.1 Hz), 7.54 (2H, d, J=8.6 Hz), 7.85(2H, d, J=8.6 Hz).

MS (m/z): 273 (M⁺+H).

Example 951-Chloro-4-[1-cyclohexyl-5-(methylsulfonyl)pentylsulfonyl]benzene

At −78° C., butyl lithium (a 1.57M hexane solution; 0.60 ml, 0.937 mmol)was added dropwise to a dimethoxyethane (3 ml) solution of1-chloro-4-(cyclohexylmethylsulfonyl)benzene (213 mg, 0.781 mmol). Afterstirring at −78° C. for 40 minutes, a dimethoxyethane (5 ml) solution ofthe 1-iodo-4-(methylsulfonyl)butane (246 mg, 0.937 mmol) obtained inReferential Example 7 was added dropwise. The temperature of thereaction mixture was raised gradually to room temperature, at whichstirring was conducted for 3 hours. Water was added to the reactionmixture, followed by extraction with ethyl acetate. The organic layerwas washed with brine and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash chromatography on a silicagel column, and the fraction obtained from the hexane:ethyl acetate(=1:1) eluate was concentrated under reduced pressure. The residue waspurified by high performance liquid chromatography (using a mixedsolvent of water/acetonitrile/formic acid) to give the title compound(54 mg, 17%) as a white solid. The resulting solid was washed withhexane and collected by filtration, whereby the title compound wasobtained as a white powder.

Melting point: 104-106° C.

IR (ATR) ν: 2925, 2854, 1583, 1475, 1444, 1423, 1392, 1309, 1288, 1268,1209, 1176, 1145, 1133, 1128, 1083, 1012, 960, 892, 825, 763, 727, 636,609, 561, 528, 495, 478, 453, 430 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.02-1.32 (5H, m), 1.44-2.00 (12H, m),2.76-2.83 (1H, m), 2.89 (3H, s), 2.97 (2H, t, J=7.0 Hz), 7.56 (2H, d,J=8.3 Hz), 7.82 (2H, d, J=8.3 Hz).

MS (m/z): 407 (M⁺+H).

Elemental Analysis for C₁₈H₂₇ClO₄S₂

Calculated: C, 53.12%; H, 6.69%; Cl, 8.71%; S, 15.76%.

Found: C, 53.11%; H, 6.49%; Cl, 8.83%; S, 15.73%.

Example 96 1-Chloro-4-(2-phenylethylsulfonyl)benzene

To an acetonitrile (10 ml) solution of 4-chlorobenzenethiol (347 mg,2.40 mmol) and (2-bromoethyl)benzene (329 μl, 2.40 mmol) was addedpotassium carbonate (498 mg, 3.60 mmol). The mixture was stirred at roomtemperature for 1.5 hours. The reaction mixture was concentrated underreduced pressure. To the residue was added hexane and the insolublematter was filtered off. The filtrate was concentrated under reducedpressure. The residue thus obtained was dissolved in methylene chloride(20 ml). To the resulting solution was added 3-chloroperbenzoic acid(870 mg, 5.04 mmol) and the mixture was stirred at room temperature for19 hours. The reaction mixture was concentrated under reduced pressure.Ethyl acetate was added. The mixture was washed successively with asaturated aqueous solution of sodium bicarbonate and brine, and driedover anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was dissolved inmethylene chloride, followed by the addition of a 1N aqueous solution ofsodium hydroxide to separate an organic layer. The organic layer wasdried over anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected tochromatography on a silica gel column and the fraction obtained from thehexane:ethyl acetate (=10:1) eluate was concentrated under reducedpressure, whereby the title compound (599 mg, 89%) was obtained as awhite solid.

IR (ATR) ν: 3023, 2923, 1600, 1581, 1496, 1473, 1454, 1394, 1299, 1276,1240, 1145, 1083, 1012, 971, 908, 823, 777, 755, 732, 694, 636, 593,570, 526, 455 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 2.98-3.10 (2H, m), 3.29-3.42 (2H, m),7.02-7.32 (5H, m), 7.55 (2H, d, J=8.6 Hz), 7.86 (2H, d, J=8.5 Hz).

MS (m/z): 281 (M⁺+H).

Example 97 4-[1-Benzyl-5-(methylsulfonyl)pentylsulfonyl]-1-chlorobenzene

At −78° C., butyl lithium (a 1.57M hexane solution; 0.57 ml, 0.902 mmol)was added dropwise to a dimethoxyethane (3 ml) solution of1-chloro-4-(2-phenylethylsulfonyl)benzene (211 mg, 0.752 mmol). Afterstirring at −78° C. for 1 hour, a dimethoxyethane (6 ml) solution of the1-iodo-4-(methylsulfonyl)butane (236 mg, 0.902 mmol) obtained inReferential Example 7 was added dropwise. The temperature of thereaction mixture was gradually elevated to room temperature, at whichstirring was conducted for 3 hours. Water was added to the reactionmixture, followed by extraction with ethyl acetate. The organic layerwas washed with brine, and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was subjected to flash chromatography on a silica gel column,and the fraction obtained from the hexane:ethyl acetate (=1:1) eluatewas concentrated under reduced pressure. The residue was purified byhigh performance liquid chromatography (using a mixed solvent ofwater/acetonitrile/formic acid) to give the title compound (72 mg, 23%)as a white solid. The resulting solid was washed with hexane andcollected by filtration, whereby the title compound was obtained as awhite powder.

Melting point: 68-70° C.

IR (ATR) ν: 3029, 2937, 2867, 1581, 1496, 1421, 1394, 1303, 1280, 1253,1187, 1133, 1083, 1041, 1012, 964, 848, 825, 759, 690, 649, 588, 553,522, 493, 455 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.40-1.77 (5H, m), 1.82-1.96 (1H, m),2.60-2.70 (1H, m), 2.75-2.91 (2H, m), 2.83 (3H, s), 3.18-3.29 (2H, m),7.04 (2H, d, J=8.3 Hz), 7.19-7.31 (3H, m), 7.56 (2H, d, J=8.6 Hz), 7.84(2H, d, J=8.6 Hz).

MS (m/z): 415 (M⁺+H).

Elemental Analysis for C₁₉H₂₃ClO₄S₂

Calculated: C, 54.99%; H, 5.59%; Cl, 8.54%; S, 15.45%.

Found: C, 55.10%; H, 5.62%; Cl, 8.50%; S, 15.56%.

Referential Example 10 (2-Chloropyridin-3-yl)methanol

At −78° C., diisobutylaluminum hydride (a 1.0M toluene solution; 4.68ml) was added dropwise to a methylene chloride (10 ml) solution of ethyl2-chloronicotinate (347 mg, 1.87 mmol). Thirty minutes later, thereaction mixture was ice cooled, followed by stirring for 15 minutes.After the completion of the reaction was confirmed, brine was added tothe reaction mixture and the temperature of the resulting mixture wasallowed to rise back to room temperature. The reaction mixture wasfiltered through Celite. The filtrate was dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure. The residue was subjected to chromatography on a silica gelcolumn and the fraction obtained from the hexane:ethyl acetate (=1:1)eluate was concentrated under reduced pressure, whereby the titlecompound (211 mg, 79%) was obtained as a white solid.

IR (ATR) ν: 3245, 2827, 1587, 1571, 1452, 1407, 1324, 1251, 1193, 1118,1087, 1041, 796, 732, 713, 655, 593, 511, 466, 414 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 2.21 (1H, t, J=5.6 Hz), 4.80 (2H, d, J=5.1Hz), 7.25-7.36 (1H, m), 7.85-7.98 (1H, m), 8.32 (1H, dd, J=4.6, 1.5 Hz).

MS (m/z): 144 (M⁺+H).

Example 98 2-Chloro-3-(4-chlorophenylsulfonylmethyl)pyridine

A chloroform (10 ml) solution of (2-chloropyridin-3-yl)methanol (204 mg,1.42 mmol) and thionyl chloride (0.31 ml, 4.26 mmol) was stirred at 50°C. for 8.5 hours. After cooling to room temperature, the reactionmixture was concentrated under reduced pressure. The residue wasdissolved in butanol (15 ml), followed by the addition of sodium4-chlorobenzenesulfinate (423 mg, 2.13 mmol) and potassium acetate (418mg, 4.26 mmol). The mixture was stirred at 70 to 80° C. for 15 hours.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. Ethyl acetate was added to the residue, and themixture was washed successively with a saturated aqueous solution ofsodium bicarbonate and brine, and dried over anhydrous sodium sulfate.After filtration, the filtrate was concentrated under reduced pressure.The residue was subjected to flash chromatography on a silica gelcolumn, and the fraction obtained from the hexane:ethyl acetate (=2:1)eluate was concentrated under reduced pressure, whereby the titlecompound (252 mg, 59%) was obtained as a white solid.

IR (ATR) ν: 3093, 2992, 2931, 1579, 1562, 1473, 1450, 1407, 1321, 1278,1249, 1195, 1153, 1133, 1116, 1083, 1060, 1010, 962, 887, 840, 813, 759,719, 686, 636, 566, 541, 501, 466, 441 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 4.54 (2H, s), 7.33 (1H, dd, J=8.8, 4.8 Hz),7.46 (2H, d, J=8.6 Hz), 7.58 (2H, d, J=8.3 Hz), 7.92 (1H, dd, J=7.7, 1.8Hz), 8.39 (1H, dd, J=4.8, 1.8 Hz).

MS (m/z): 302 (M⁺+H).

Example 992-Chloro-3-[1-(4-chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]pyridine

A toluene (10 ml) solution of2-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (56 mg, 0.184 mmol),the 4-(methylsulfonyl)-1-butanol (56 mg, 0.368 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (89 mg,0.368 mmol) was heated under reflux for 19 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasadded with 4-(methylsulfonyl)-1-butanol (56 mg, 0.368 mmol) andcyanomethylenetri-n-butylphosphorane (89 mg, 0.368 mmol), followed byheating under reflux for 5 hours under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue was subjected to flash chromatography on asilica gel column, and the fraction obtained from the hexane:ethylacetate (=1:2) eluate was concentrated under reduced pressure, wherebythe title compound (76 mg, 95%) was obtained as an amorphous substance.

IR (ATR) ν: 3085, 2931, 1579, 1562, 1475, 1407, 1278, 1184, 1139, 1083,1012, 962, 908, 821, 752, 732, 690, 626, 574, 520, 466 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.32-1.55 (2H, m), 1.80-1.99 (2H, m),2.10-2.25 (1H, m), 2.40-2.63 (1H, m), 2.88 (3H, s), 2.96 (2H, t, J=7.8Hz), 4.79 (1H, dd, J=11.0, 4.2 Hz), 7.32-7.42 (3H, m), 7.48 (2H, d,J=8.3 Hz), 8.04 (1H, dd, J=7.8, 1.7 Hz), 8.36 (1H, dd, J=4.8, 1.8 Hz).

MS (m/z): 436 (M⁺+H).

HRMS (FAB) for C₁₇H₂₀O₄NCl₂S₂ (M⁺+H)

Calculated: 436.0211

Found: 436.0195

Referential Example 11 (2-Fluoropyridin-3-yl)methanol

Under ice cooling, trimethylsilyldiazomethane (0.72 ml) was added to asolution of 2-fluoronicotinic acid (210 mg, 1.49 mmol) intetrahydrofuran (15 ml) and methanol (1 ml), and the mixture was stirredfor 30 minutes. The reaction mixture was concentrated under reducedpressure. The residue was subjected to chromatography on a silica gelcolumn, and the fraction obtained from the hexane:ethyl acetate (=4:1)eluate was concentrated under reduced pressure.

At −78° C., diisobutylaluminum hydride (a 1.0M toluene solution; 1.60ml) was added dropwise to a methylene chloride (10 ml) solution of theresidue (95 mg, 0.612 mmol). Fifteen minutes later, the reaction mixturewas ice cooled and stirred for 15 minutes. After completion of thereaction was confirmed, brine was added and the temperature of thereaction mixture was allowed to rise back gradually to room temperature.The reaction mixture was filtered through Celite. The filtrate was driedover anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected tochromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate (=2:1) eluate was concentrated under reducedpressure, whereby the title compound (55 mg, 71%) was obtained as awhite solid.

IR (ATR) ν: 3338, 2873, 1650, 1608, 1430, 1365, 1241, 1176, 1108, 1045,1020, 858, 800, 775, 744, 619, 572, 539, 520 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 4.78 (2H, s), 7.18-7.25 (1H, m), 7.85-7.97(1H, m), 8.14 (1H, d, J=4.9 Hz).

MS (m/z): 128 (M⁺+H).

Example 100 3-(4-Chlorophenylsulfonylmethyl)-2-fluoropyridine

A chloroform (10 ml) solution of (2-fluoropyridin-3-yl)methanol (49 mg,0.385 mmol) and thionyl chloride (0.14 ml, 1.93 mmol) was stirred at 50°C. for 3.5 hours. After cooling to room temperature, the reactionmixture was concentrated under reduced pressure. The residue thusobtained was dissolved in butanol (5 ml), followed by the addition ofsodium 4-chlorobenzenesulfinate (92 mg, 0.462 mmol) and potassiumacetate (76 mg, 0.770 mmol). The mixture was stirred at 70 to 80° C. for12 hours. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. Ethyl acetate was added to theresidue, and the mixture was washed successively with a saturatedaqueous solution of sodium bicarbonate and brine, and then, dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column. The fraction obtained from thehexane:ethyl acetate (=2:1) eluate was concentrated under reducedpressure, whereby the title compound (59 mg, 54%) was obtained as awhite solid.

IR (ATR) ν: 3097, 2989, 2933, 1643, 1606, 1573, 1469, 1434, 1409, 1392,1321, 1276, 1240, 1184, 1170, 1149, 1083, 1010, 956, 902, 842, 813, 779,763, 725, 696, 640, 582, 541, 522, 480, 445 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 4.38 (2H, s), 7.21-7.30 (1H, m), 7.47 (2H, d,J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz), 7.87-7.94 (1H, m), 8.19-8.25 (1H, m).

MS (m/z): 286 (M⁺+H).

Example 1013-[1-(4-Chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]-2-fluoropyridine

A toluene (10 ml) solution of3-(4-chlorophenylsulfonylmethyl)-2-fluoropyridine (53 mg, 0.185 mmol),the 4-(methylsulfonyl)-1-butanol (56 mg, 0.370 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (89 mg,0.370 mmol) was heated under reflux for 22 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column. The fraction obtained from thehexane:ethyl acetate (=1:2) eluate was concentrated under reducedpressure, whereby the title compound (42 mg, 54%) was obtained as anamorphous substance.

IR (ATR) ν: 3089, 2950, 2865, 1604, 1573, 1467, 1434, 1394, 1313, 1290,1270, 1249, 1199, 1147, 1126, 1083, 1012, 960, 906, 854, 815, 757, 738,703, 628, 576, 536, 464, 437 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.38-1.55 (2H, m), 1.85-1.99 (2H, m),2.14-2.28 (1H, m), 2.45-2.60 (1H, m), 2.88 (3H, s), 2.96 (2H, t, J=7.8Hz), 4.46 (1H, dd, J=11.2, 4.2 Hz), 7.25-7.32 (1H, m), 7.41 (2H, d,J=8.6 Hz), 7.50 (2H, d, J=8.3 Hz), 7.98-8.04 (1H, m), 8.20 (1H, d, J=4.9Hz).

MS (m/z): 420 (M⁺+H).

HRMS (FAB) for C₁₇H₂₀O₄NClFS₂ (M⁺+H)

Calculated: 420.0506

Found: 420.0509

Example 102 2,5-Dichloro-3-(4-chlorophenylsulfonylmethyl)pyridine

At −78° C., diisobutylaluminum hydride (a 1M hexane solution; 1.92 ml)was added dropwise to a methylene chloride (10 ml) solution of methyl2,5-dichloronicotinate (188 mg, 0.912 mmol). The resulting mixture wasstirred at 0° C. for 30 minutes. The reaction mixture was added withbrine, and the mixture was filtered through Celite. The filtrate wasdried over anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected tochromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate (=3:1) eluate was concentrated under reducedpressure. To a chloroform (10 ml) solution of the residue (128 mg) wasadded thionyl chloride (0.26 ml, 3.60 mmol), followed by stirring at 50°C. for 6.5 hours. After cooling to room temperature, the reactionmixture was concentrated under reduced pressure. The residue wasdissolved in butanol (10 ml). To the resulting solution were addedsodium 4-chlorobenzenesulfinate (171 mg, 0.863 mmol) and potassiumacetate (212 mg, 2.16 mmol) and the mixture was stirred at 70° C. for 19hours. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. Ethyl acetate was added to theresidue, followed by successive washing with water and brine and dryingover anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The resulting solid was washed withhexane-diisopropyl ether, and collected by filtration, whereby the titlecompound (108 mg, 35%) was obtained as a white powder.

IR (ATR) ν: 3091, 3064, 2998, 2933, 1581, 1550, 1473, 1419, 1392, 1317,1280, 1255, 1234, 1170, 1135, 1085, 1068, 1010, 910, 833, 821, 767, 727,709, 646, 582, 539, 507, 464, 430 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 4.49 (2H, s), 7.49 (2H, d, J=8.6 Hz), 7.62(2H, d, J=8.8 Hz), 7.90 (1H, d, J=2.5 Hz), 8.35 (1H, d, J=2.5 Hz).

MS (m/z): 336 (M⁺+H).

Example 1032,5-Dichloro-3-[1-(4-chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]pyridine

A toluene (10 ml) solution of2,5-dichloro-3-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.208mmol), the 4-(methylsulfonyl)-1-butanol (95 mg, 0.624 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (151 mg,0.624 mol) was heated under reflux for 3 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate (=1:1) eluate was concentrated under reducedpressure, whereby the title compound (74 mg, 76%) was obtained as anamorphous substance.

IR (ATR) ν: 3091, 3060, 2931, 1581, 1546, 1475, 1413, 1313, 1278, 1209,1124, 1083, 1049, 1012, 964, 906, 871, 831, 754, 705, 628, 588, 532, 468cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.38-1.52 (2H, m), 1.83-1.98 (2H, m),2.08-2.20 (1H, m), 2.49-2.60 (1H, m), 2.88 (3H, s), 2.97 (2H, t, J=7.8Hz), 4.72 (1H, dd, J=10.9, 4.0 Hz), 7.43 (2H, d. J=8.6 Hz), 7.53 (2H, d,J=8.6 Hz), 8.00 (1H, d, J=2.5 Hz), 8.31 (1H, d, J=2.5 Hz).

MS (m/z): 470 (M⁺+H).

Elemental Analysis for C₁₇H₁₈Cl₃NO₄S₂.0.25H₂O

Calculated: C, 42.96%; H, 3.92%; Cl, 22.38%; N, 2.95%; S, 13.49%.

Found: C, 43.02%; H, 3.81%; Cl, 22.54%; N, 3.01%; S, 13.50%.

Example 104 4-Chloro-3-(4-chlorophenylsulfonylmethyl)pyridine

A carbon tetrachloride (15 ml) suspension of 4-chloro-3-methylpyridinehydrochloride (402 mg, 2.45 mmol), N-chlorosuccinic acid imide (327 mg,2.45 mmol) and 2,2′-azobis(2-methylpropionitrile) (30 mg, 0.183 mmol)was heated under reflux for 13 hours under a nitrogen atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue was dissolved in butanol (10 ml), followedby the addition of sodium 4-chlorophenylsulfinate (487 mg, 2.45 mmol)and potassium acetate (481 mg, 4.90 mmol). The mixture was stirred at70° C. for 24 hours. The reaction mixture was cooled to roomtemperature, followed by concentration under reduced pressure. Ethylacetate was added to the residue. The mixture was washed successivelywith a saturated aqueous solution of sodium bicarbonate and brine andthen, dried over anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The residue wassubjected to chromatography on a silica gel column, and the fractionobtained from the hexane:ethyl acetate (=2:1) eluate was concentratedunder reduced pressure, whereby the title compound (130 mg, 18%) wasobtained as a white solid.

IR (ATR) ν: 3060, 2917, 1708, 1573, 1556, 1475, 1413, 1403, 1311, 1280,1232, 1189, 1155, 1120, 1079, 1012, 933, 890, 854, 833, 817, 777, 744,721, 694, 632, 574, 557, 514, 460

¹H-NMR (400 MHz, CDCl₃) δ: 4.56 (2H, s), 7.28 (1H, d, J=5.4 Hz), 7.48(2H, d, J=8.3 Hz), 7.63 (2H, d, J=8.5 Hz), 8.49 (1H, d, J=5.4 Hz), 8.54(1H, s).

MS (m/z): 302 (M⁺+H).

Example 1054-Chloro-3-[1-[(4-chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]pyridine

A toluene (10 ml) solution of4-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (80 mg, 0.265 mmol),the 4-(methylsulfonyl)-1-butanol (81 mg, 0.529 mmol) obtained inReferential Example 3 and cyanomethylenetri-n-butylphosphorane (128 mg,0.529 mol) was heated under reflux under an argon atmosphere for 3 days.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. The residue was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate (=1:5) eluate was concentrated under reducedpressure to give the title compound (74 mg, 64%) as a white solid. Theresulting solid was washed with ether and then, collected by filtration,whereby the title compound was obtained as a white powder.

Melting point: 156-157° C.

IR (ATR) ν: 3087, 3064, 3018, 2933, 1571, 1473, 1409, 1311, 1270, 1207,1149, 1076, 1014, 968, 906, 831, 794, 752, 700, 617, 576, 536, 497, 466cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.35-1.60 (2H, m), 1.80-1.99 (2H, m),2.20-2.33 (1H, m), 2.51-2.65 (1H, m), 2.88 (3H, s), 2.90-3.00 (2H, m),4.80 (1H, dd, J=10.9, 3.8 Hz), 7.20 (1H, d, J=5.4 Hz), 7.40 (2H, d,J=8.5 Hz), 7.52 (2H, d, J=8.6 Hz), 8.46 (1H, d, J=5.4 Hz), 8.80 (1H, s).

MS (m/z): 436 (M⁺+H).

Elemental Analysis for C₁₇H₁₉Cl₂NO₄S₂

Calculated: C, 46.79%; H, 4.39%; Cl, 16.25%; N, 3.21%; S, 14.70%.

Found: C, 46.88%; H, 4.40%; Cl, 16.14%; N, 3.30%; S, 14.52%.

Example 1063-[6-(tert-Butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]hexyl]-2-chloropyridine

A toluene (5 ml) solution of the2-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (200 mg, 0.662 mmol)obtained in Example 98, 5-(tert-butyldimethylsilyloxy)pentanol (288 mg,1.32 mmol) and cyanomethylenetri-n-butylphosphorane (318 mg, 1.32 mmol)was heated under reflux for 22 hours under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue was subjected to flash chromatography on asilica gel column, and the fraction obtained from the 15% ethylacetate/hexane eluate was concentrated under reduced pressure, wherebythe title compound (307 mg, 92%) was obtained as a colorless oil.

IR (ATR) ν: 2929, 2856, 1581, 1562, 1473, 1409, 1394, 1359, 1321, 1278,1253, 1184, 1149, 1083, 1058, 1012, 985, 921, 833, 775, 752, 734, 690,626, 570, 534, 466 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.01 (6H, s), 0.86 (9H, s), 1.12-1.50 (6H,m), 2.07-2.20 (1H, m), 2.45-2.57 (1H, m), 3.53 (2H, t, J=6.1 Hz), 4.78(1H, dd, J=11.4, 3.8 Hz), 7.31-7.40 (3H, m), 8.79 (2H, d, J=7.5 Hz),8.03 (1H, dd, J=7.8, 2.0 Hz), 8.34 (1H, dd, J=4.6, 2.0 Hz).

MS (m/z): 502 (M⁺+H)

Example 1076-(4-Chlorophenylsulfonyl)-6-(2-chloropyridin-3-yl)-1-hexanol

Under ice cooling, tetrabutylammonium fluoride (a 1 mol/ltetrahydrofuran solution; 0.70 ml) was added to a tetrahydrofuran (10ml) solution of3-[6-(tert-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]hexyl]-2-chloropyridine(294 mg, 0.585 mmol). The resulting mixture was stirred at roomtemperature for 24 hours. The reaction mixture was concentrated underreduced pressure. Ethyl acetate was added to the residue, and themixture was washed successively with water and brine, and dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected tochromatography on a silica gel column. The fraction obtained from thehexane:ethyl acetate (=1:1) eluate was concentrated under reducedpressure, whereby the title compound (212 mg, 93%) was obtained as acolorless oil.

IR (ATR) ν: 3400, 2933, 2859, 1579, 1562, 1475, 1407, 1394, 1315, 1278,1184, 1145, 1083, 1058, 1012, 821, 752, 734, 690, 626, 605, 570, 534,466, 412 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.15-1.65 (8H, m), 2.07-2.20 (1H, m),2.47-2.58 (1H, m), 3.59 (2H, t, J=6.4 Hz), 4.79 (1H, dd, J=11.4, 3.8Hz), 7.30-7.42 (3H, m), 7.48 (2H, d, J=8.8 Hz), 8.03 (1H, dd, J=7.8, 2.0Hz), 8.34 (1H, dd, J=4.1, 1.7 Hz).

MS (m/z): 388 (M⁺+H).

HRMS (FAB) for C₁₇H₂₀O₃NCl₂S (M⁺+H)

Calculated: 388.0541

Found: 388.0561

Example 108 2-Chloro-3-[1-(4-chlorophenylsulfonyl)cycloheptyl]pyridine

At −78° C., butyl lithium (a 1.57M hexane solution; 0.62 ml, 0.966 mmol)was added dropwise to a dimethoxyethane (5 ml) solution of the2-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (146 mg, 0.483 mmol)obtained in Example 98. At −78° C., the resulting mixture was stirredfor 20 minutes, followed by the addition of 1,6-diiodohexane (0.095 ml,0.580 mmol). The temperature of the reaction mixture was graduallyraised to room temperature, at which stirring was performed for 4 hours.Water was added to the reaction mixture, followed by extraction withethyl acetate. The organic layer was washed with brine and then driedover anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe 15% ethyl acetate/hexane eluate was concentrated under reducedpressure. The residue thus obtained was purified by high performanceliquid chromatography (using a mixed solvent ofwater/acetonitrile/formic acid) to yield the title compound (60 mg, 32%)as a white solid. The resulting solid was washed with hexane-ether andthen collected by filtration, whereby the title compound was obtained asa white powder.

Melting point: 168-169° C.

IR (ATR) ν: 2929, 2861, 1573, 1558, 1473, 1454, 1394, 1303, 1276, 1139,1083, 1066, 1008, 840, 800, 748, 711, 646, 613, 574, 522, 470, 412 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.30-1.50 (4H, m), 1.50-1.66 (2H, m),1.85-1.98 (2H, m), 2.33-2.48 (2H, m), 2.94-3.10 (2H, m), 7.28-7.37 (3H,m), 7.40 (2H, d, J=8.8 Hz), 7.93 (1H, dd, J=8.1, 1.7 Hz), 8.38 (1H, dd,J=4.5, 1.8 Hz).

MS (m/z): 384 (M⁺+H).

Elemental Analysis for C₁₈H₁₉Cl₂NO₂S

Calculated: C, 56.25%; H, 4.98%; Cl, 18.45%; N, 3.64%; S, 8.34%.

Found: C, 56.20%; H, 4.85%; Cl, 18.50%; N, 3.73%; S, 8.46%.

Example 109 2-Chloro-3-[1-(4-chlorophenylsulfonyl)cyclohexyl]pyridine

At −78° C., butyl lithium (a 1.57M hexane solution; 0.66 ml, 1.03 mmol)was added dropwise to a dimethoxyethane (5 ml) solution of the2-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (156 mg, 0.516 mmol)obtained in Example 98. At −78° C., the resulting mixture was stirredfor 20 minutes, followed by the addition of 1,5-diiodopentane (0.092 ml,0.619 mmol). The temperature of the reaction mixture was graduallyelevated to room temperature, at which stirring was performed for 15hours. Water was added to the reaction mixture, followed by extractionwith ethyl acetate. The organic layer was washed with brine and thendried over anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe 15% ethyl acetate/hexane eluate was concentrated under reducedpressure. The residue thus obtained was purified by high performanceliquid chromatography (using a mixed solvent ofwater/acetonitrile/formic acid) to give the title compound (72 mg, 38%)as a white solid. The resulting solid was washed with hexane-ether andthen collected by filtration, whereby the title compound was obtained asa white powder.

Melting point: 129-131° C.

IR (ATR) ν: 2929, 2861, 1575, 1558, 1475, 1446, 1392, 1303, 1278, 1143,1130, 1083, 1054, 1010, 910, 875, 833, 809, 754, 742, 742, 732, 703,646, 617, 580, 495, 458 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.05-1.30 (2H, m), 1.33-1.50 (1H, m),1.52-1.70 (1H, m), 1.75-1.90 (2H, m), 2.02-2.30 (2H, m), 2.65-3.60 (2H,m), 7.29-7.39 (3H, m), 7.41 (2H, d, J=8.8 Hz), 8.05 (1H, dd, J=8.1, 1.7Hz), 8.39 (1H, dd, J=4.5, 1.8 Hz).

MS (m/z): 370 (M⁺+H).

Elemental Analysis for C₁₇H₁₇Cl₂NO₂S

Calculated: C, 55.14%; H, 4.63%; Cl, 19.15%; N, 3.78%; S, 8.66%.

Found: C, 55.06%; H, 4.55%; Cl, 19.15%; N, 3.87%; S, 8.76%.

Example 110 4-Chloro-3-[1-(4-chlorophenylsulfonyl)cyclohexyl]pyridine

At −78° C., butyl lithium (a 1.57M hexane solution; 0.58 ml, 0.913 mmol)was added dropwise to a dimethoxyethane (5 ml) solution of the4-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (138 mg, 0.457 mmol)obtained in Example 104. At −78° C., the resulting mixture was stirredfor 20 minutes and then 1,5-diiodopentane (0.068 ml, 0.457 mmol) wasadded thereto. The temperature of the reaction mixture was graduallyraised to room temperature, at which stirring was performed for 17hours. Water was added to the reaction mixture, followed by extractionwith ethyl acetate. The organic layer was washed with brine and thendried over anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate (=2:1) eluate was concentrated under reducedpressure. The residue thus obtained was purified by high performanceliquid chromatography (using a mixed solvent ofwater/acetonitrile/formic acid) to give the title compound (30 mg, 18%)as a white solid. The resulting solid was washed with ether and thencollected by filtration, whereby the title compound was obtained as awhite powder.

Melting point: 145-147° C.

IR (ATR) ν: 2929, 2863, 1579, 1469, 1452, 1392, 1346, 1305, 1280, 1270,1211, 1143, 1081, 1012, 975, 937, 910, 871, 823, 794, 754, 725, 680,617, 582, 563, 547, 507, 468 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.10-1.30 (2H, m), 1.32-1.50 (1H, m),1.60-1.69 (1H, m), 1.78-1.89 (2H, m), 2.01-2.22 (2H, m), 2.70-3.00 (1H,m), 3.30-3.70 (1H, m), 7.23 (1H, d, J=5.4 Hz), 7.35 (2H, d, J=8.8 Hz),7.40 (2H, d, J=8.8 Hz), 8.41 (1H, d, J=5.1 Hz), 8.57 (1H, s).

MS (m/z): 370 (M⁺+H).

Elemental Analysis for C₁₇H₁₇Cl₂NO₂S

Calculated: C, 55.14%; H, 4.63%; Cl, 19.15%; N, 3.78%; S, 8.66%.

Found: C, 54.99%; H, 4.61%; Cl, 19.06%; N, 3.89%; S, 8.72%.

Example 111 4-(4-Chlorophenylsulfonylmethyl)thiazole

To 1-propanol (10 ml) were added sodium 4-chlorobenzenesulfinate (359mg, 1.81 mmol), 4-(chloromethyl)thiazole hydrochloride (307 mg, 1.81mmol) and potassium acetate (354 mg, 3.61 mmol) and the mixture wasstirred at 70° C. for 21 hours. After cooling the reaction mixture toroom temperature, the solvent was concentrated under reduced pressure.Ethyl acetate was added to the residue. The mixture was washedsuccessively with water and brine and then dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure. The residue was subjected to flash chromatography on a silicagel column, and the fraction obtained from the hexane:ethyl acetateeluate (=3:2) was concentrated under reduced pressure. The resultingsolid was washed with hexane-ether and then collected by filtration,whereby the title compound (154 mg, 31%) was obtained as a white powder.

IR (ATR) ν: 3102, 2969, 2917, 1575, 1504, 1473, 1413, 1396, 1334, 1309,1257, 1220, 1159, 1122, 1081, 1012, 948, 898, 875, 831, 821, 784, 723,657, 593, 561, 541, 478, 451, 418 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 4.64 (2H, s), 7.40-7.50 (3H, m), 7.62 (2H, d,J=8.8 Hz), 8.66 (1H, s).

MS (m/z): 274 (M⁺+H).

Example 1124-[1-(4-Chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]thiazole

To butanol (5 ml) were added sodium 4-chlorobenzenesulfinate (113 mg,0.569 mmol), 4-(chloromethyl)thiazole hydrochloride (97 mg, 0.569 mmol)and potassium acetate (112 mg, 1.14 mmol) and the resulting mixture wasstirred at 70° C. for 11 hours. After cooling the reaction mixture toroom temperature, the solvent was concentrated under reduced pressure.Ethyl acetate was added to the residue. The resulting mixture was washedwith a saturated aqueous solution of sodium bicarbonate and then, driedover anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. A toluene (10 ml) solution of theresulting residue, the 4-(methylsulfonyl)-1-butanol (130 mg, 0.853 mmol)obtained in Referential Example 3 andcyanomethylenetri-n-butylphosphorane (206 mg, 0.853 mmol) was heatedunder reflux for 15 hours under an argon atmosphere. After cooling toroom temperature, the reaction mixture was concentrated under reducedpressure. The residue was subjected to flash chromatography on a silicagel column, and the fraction obtained from the hexane:ethyl acetate(=1:3) eluate was concentrated under reduced pressure to give the titlecompound (111 mg, 48%) as a white solid. The white solid was washed withhexane-ether and then collected by filtration, whereby the titlecompound was obtained as a white powder.

Melting point: 123-125° C.

IR (ATR) ν: 3102, 2937, 1581, 1508, 1475, 1421, 1392, 1311, 1295, 1274,1234, 1197, 1145, 1130, 1085, 1014, 964, 931, 877, 850, 821, 767, 750,709, 665, 557, 530, 487, 455, 420 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.35-1.55 (2H, m), 1.80-1.98 (2H, m),2.24-2.39 (1H, m), 2.39-2.50 (1H, m), 2.87 (3H, s), 2.91-3.01 (2H, m),4.48 (1H, dd, J=11.2, 3.9 Hz), 7.38-7.45 (3H, m), 7.47 (2H, d, J=8.6Hz), 8.65 (1H, s).

MS (m/z): 408 (M⁺+H).

Elemental Analysis for C₁₅H₁₈ClNO₄S₃

Calculated: C, 44.16%; H, 4.45%; Cl, 8.69%; N, 3.43%; S, 23.58%.

Found: C, 44.25%; H, 4.34%; Cl, 8.58%; N, 3.54%; S, 23.82%.

Example 113 5-(4-Chlorophenylsulfonylmethyl)thiazole

A carbon tetrachloride (15 ml) suspension of 5-methylthiazole (380 mg,3.83 mmol), N-chlorosuccinic imide (511 mg, 3.83 mmol),2,2′-azobis(2-methylpropionitrile) (62 g, 0.380 mmol) and acetic acid(0.22 ml, 3.83 mmol) was heated under reflux for 18 hours under anitrogen atmosphere. The reaction mixture was cooled to room temperatureand then, concentrated under reduced pressure. The resulting residue wasdissolved in butanol (10 ml). To the resulting solution were addedsodium 4-chlorophenylsulfinate (761 mg, 3.83 mmol) and potassium acetate(376 mg, 3.83 mmol), followed by stirring at 70° C. for 23 hours. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. Ethyl acetate was added to the residue. The mixturewas washed successively with water and brine and then dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected tochromatography on a silica gel column. The fraction obtained from thehexane:ethyl acetate (=1:1) eluate was concentrated under reducedpressure, whereby the title compound (76 mg, 7.2%) was obtained as apale yellow solid.

IR (ATR) ν: 3085, 2975, 2915, 1671, 1577, 1521, 1473, 1392, 1313, 1253,1193, 1143, 1081, 1012, 968, 894, 873, 836, 773, 728, 705, 651, 620,605, 565, 543, 476, 443 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 4.57 (2H, s), 7.49 (2H, d, J=8.8 Hz), 7.57(1H, s), 7.65 (2H, d, J=8.6 Hz), 8.81 (1H, s).

MS (m/z): 274 (M⁺+H).

Example 1145-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]thiazole

A toluene (10 ml) solution of 5-(4-chlorophenylsulfonylmethyl)thiazole(51 mg, 0.186 mmol), the 4-(methylsulfonyl)-1-butanol (57 mg, 0.372mmol) obtained in Referential Example 3 andcyanomethylenetri-n-butylphosphorane (90 mg, 0.372 mol) was heated underreflux for 21 hours under an argon atmosphere. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The residue was subjected to flash chromatography on a silicagel column. The fraction obtained from the methylene chloride:ethylacetate (=1:2) eluate was concentrated under reduced pressure to givethe title compound (53 mg, 70%) as a white solid. The resulting whitesolid was washed with hexane-ether, and then filtered, whereby the titlecompound was obtained as a white powder.

Melting point: 95-96° C.

IR (ATR) ν: 3099, 3021, 2942, 1575, 1513, 1473, 1392, 1351, 1299, 1272,1240, 1201, 1174, 1137, 1085, 1012, 966, 914, 873, 827, 777, 746, 703,634, 613, 566, 528, 470 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.445-1.60 (2H, m), 1.81-1.99 (2H, m),2.00-2.12 (1H, m), 2.50-2.61 (1H, m), 2.89 (3H, s), 2.92-3.01 (2H, m),4.41 (1H, dd, J=11.1, 3.5 Hz), 7.43 (2H, d, J=8.5 Hz), 7.47 (1H, s),7.52 (2H, d, J=8.5 Hz), 8.82 (1H, s).

MS (m/z): 408 (M⁺+H).

Elemental Analysis for C₁₅H₁₈ClNO₄S₃

Calculated: C, 44.16%; H, 4.45%; Cl, 8.69%; N, 3.43%; S, 23.58%.

Found: C, 44.44%; H, 4.38%; Cl, 8.75%; N, 3.53%; S, 23.41%.

Referential Example 12 Thiazole-2-methanol

While stirring under ice cooling, sodium borohydride (242 mg, 6.40 mmol)was added to a methanol (10 ml) solution of 2-formylthiazole (483 mg,4.27 mmol). After completion of the reaction was confirmed, water wasadded to the reaction mixture. The resulting mixture was concentratedunder reduced pressure. Water and ethyl acetate were added to theresidue to separate the organic layer. The organic layer was washed withbrine and then dried over anhydrous sodium sulfate. After filtration,the filtrate was concentrated under reduced pressure. The residue wassubjected to chromatography on a silica gel column. The fractionobtained from the hexane:ethyl acetate (=1:1) eluate was concentratedunder reduced pressure, whereby the title compound (324 mg, 66%) wasobtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 3.30-3.70 (1H, m), 5.14 (2H, s), 7.32 (1H, d,J=3.4 Hz), 7.74 (1H, d, J=3.2 Hz).

MS (m/z): 116 (M⁺+H).

Example 115 2-(4-Chlorophenylsulfonylmethyl)thiazole

To a chloroform (15 ml) solution of thiazole-2-methanol (171 mg, 1.49mmol) was added thionyl chloride (0.33 ml, 4.47 mmol) and the resultingmixture was stirred at 50° C. for 11 hours. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in butanol (10 ml). To the resultingsolution were added sodium 4-chlorobenzenesulfinate (296 mg, 1.49 mmol)and potassium acetate (292 mg, 2.98 mmol). The mixture was stirred at70° C. for 24 hours. After cooling to room temperature, the reactionmixture was concentrated under reduced pressure. Ethyl acetate was addedto the residue. The mixture was washed successively with water and brineand then, dried over anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The residue wassubjected to chromatography on a silica gel column. The fractionobtained from the hexane:ethyl acetate (=1:1) eluate was concentratedunder reduced pressure, whereby the title compound (169 mg, 41%) wasobtained as a pale yellow solid.

IR (ATR) ν: 2967, 2913, 1573, 1498, 1475, 1394, 1317, 1280, 1218, 1184,1147, 1081, 1062, 1012, 966, 887, 825, 775, 763, 730, 700, 630, 599,563, 549, 478, 447 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 4.79 (2H, s), 7.42 (1H, d, J=3.2 Hz), 7.47(2H, d, J=8.6 Hz), 7.64 (2H, d, J=8.8 Hz), 7.72 (1H, d, J=3.4 Hz).

MS (m/z): 274 (M⁺+H).

Example 1162-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]thiazole

A toluene (10 ml) solution of 2-(4-chlorophenylsulfonylmethyl)thiazole(75 mg, 0.274 mmol), the 4-(methylsulfonyl)-1-butanol (83 mg, 0.548mmol) obtained in Referential Example 3 andcyanomethylenetri-n-butylphosphorane (132 mg, 0.548 mol) was heatedunder reflux for 20 hours under an argon atmosphere. After cooling toroom temperature, the reaction mixture was concentrated under reducedpressure. The residue was subjected to flash chromatography on a silicagel column. The fraction obtained from the methylene chloride:ethylacetate (=1:2) eluate was concentrated under reduced pressure to givethe title compound (87 mg, 78%) as a white solid. The resulting solidwas washed with ether and then, collected by filtration, whereby thetitle compound was obtained as a white powder.

Melting point: 118-119° C.

IR (ATR) ν: 3137, 3006, 2913, 1583, 1496, 1471, 1388, 1357, 1315, 1284,1238, 1203, 1135, 1083, 1043, 1010, 975, 877, 842, 804, 765, 736, 705,642, 601, 572, 526, 468, 439 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.40-1.62 (2H, m), 1.80-1.99 (2H, m),2.22-2.35 (1H, m), 2.48-2.58 (1H, m), 2.88 (3H, s), 2.92-3.00 (2H, m),4.61 (1H, dd, J=11.2, 3.7 Hz), 7.39-7.47 (3H, m), 7.51 (2H, d, J=8.5Hz), 7.68 (1H, d, J=3.4 Hz).

MS (m/z): 408 (M⁺+H).

Elemental Analysis for C₁₅H₁₈ClNO₄S₃

Calculated: C, 44.16%; H, 4.45%; Cl, 8.69%; N, 3.43%; S, 23.58%.

Found: C, 44.32%; H, 4.40%; Cl, 8.74%; N, 3.54%; S, 24.04%.

Example 117 5-(4-Chlorophenylsulfonylmethyl)oxazole

Thionyl chloride (188 μl, 2.57 mmol) was added to a chloroform (10 ml)solution of oxazol-5-ylmethanol (85 mg, 0.858 mmol). The resultingmixture was stirred at 50° C. for 1.5 hours. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The residue thus obtained was dissolved in butanol (10 ml). Tothe resulting solution were added sodium 4-chlorobenzenesulfinate (170mg, 0.858 mmol), potassium acetate (252 mg, 2.57 mmol) andtetrabutylammonium iodide (15 mg), followed by stirring at 70° C. for 3days. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. Ethyl acetate was added to theresidue. The mixture was washed successively with water and brine andthen, dried over anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The residue wassubjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate (=1:1) fraction wasconcentrated under reduced pressure, whereby the title compound (81 mg,37%) was obtained as a white solid.

IR (ATR) ν: 3141, 3085, 2983, 2921, 1475, 1506, 1490, 1475, 396, 1319,1284, 1263, 1213, 1178, 1151, 1110, 968, 923, 69, 823, 769, 746, 700,644, 559, 541, 482, 455, 422 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 4.47 (2H, s), 7.02 (1H, s), 7.52 (2H, d,J=8.8 Hz), 7.70 (2H, d, J=8.8 Hz), 7.82 (1H, s).

MS (m/z): 258 (M⁺+H).

Example 1185-[1-(4-Chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]oxazole

A toluene (10 ml) solution of 5-(4-chlorophenylsulfonylmethyl)oxazole(65 mg, 0.252 mmol), the 4-(methylsulfonyl)-1-butanol (77 mg, 0.504mmol) obtained in Referential Example 3 andcyanomethylenetri-n-butylphosphorane (122 mg, 0.504 mmol) was heatedunder reflux for 15 hours under an argon atmosphere. After cooling toroom temperature, the reaction mixture was added with the4-(methylsulfonyl)-1-butanol (77 mg, 0.504 mmol) obtained in ReferentialExample 3 and cyanomethylenetri-n-butylphosphorane (122 mg, 0.504 mmol),followed by heating under reflux for 25 hours under an argon atmosphere.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. The residue was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate (=1:3) eluate was concentrated under reducedpressure to give the title compound (82 mg, 83%) as a white solid. Theresulting white solid was washed with hexane and then, collected byfiltration, whereby the title compound was obtained as a white powder.

Melting point: 164-166° C.

IR (ATR) ν: 3139, 2937, 1583, 1504, 1475, 1394, 1311, 1276, 1193, 1147,1128, 1108, 1085, 1054, 1012, 968, 946, 919, 871, 854, 831, 771, 754,707, 649, 622, 553, 532, 491, 462 cm¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.43-1.60 (2H, m), 1.80-1.99 (2H, m),2.06-2.20 (1H, m), 2.39-2.49 (1H, m), 2.89 (3H, s), 2.94-3.01 (2H, m),4.29 (1H, dd, J=11.1, 4.0 Hz), 6.96 (1H, s), 7.48 (2H, d, J=8.3 Hz),7.57 (2H, d, J=8.6 Hz), 7.79 (1H, s).

MS (m/z): 392 (M⁺+H).

Elemental Analysis for C₁₅H₁₈ClNO₅S₂

Calculated: C, 45.97%; H, 4.63%; Cl, 9.05%; N, 3.57%; S, 16.36%.

Found: C, 45.98%; H, 4.79%; Cl, 8.96%; N, 3.66%; S, 16.29%.

Example 119 4-(4-Chlorophenylsulfonylmethyl)pyridine

Under heating, a 1-propanol (50 ml) solution of 4-chloromethylpyridinehydrochloride (1.26 g, 7.65 mmol), sodium 4-chlorobenzenesulfinate (1.52g, 7.65 mmol) and potassium acetate (1.50 g, 15.3 mmol) was stirred at70° C. for 8 hours. After cooling to room temperature, the reactionmixture was concentrated under reduced pressure. The residue wasfiltered through a short column (silica gel, ethyl acetate) and theeluate was concentrated under reduced pressure. The residue wassubjected to chromatography on a silica gel column, and the fractionobtained from the hexane:ethyl acetate (=2:3) eluate was concentratedunder reduced pressure, whereby the title compound (1.26 g, 62%) wasobtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 4.29 (2H, s), 7.06 (2H, d, J=6.1 Hz), 7.47(2H, d, J=8.8 Hz), 7.59 (2H, d, J=8.5 Hz), 8.57 (2H, d, J=6.1 Hz).

MS (m/z): 268 (M⁺+H).

Example 120 4-[1-(4-Chlorophenylsulfonyl)pentyl]pyridine

At −78° C., butyl lithium (a 1.57M hexane solution; 0.29 ml, 0.448 mmol)was added dropwise to a tetrahydrofuran (5 ml) solution of4-(4-chlorophenylsulfonylmethyl)pyridine (100 mg, 0.374 mmol). At −78°C., the resulting mixture was stirred for 10 minutes. Iodobutane (51 μl,0.448 mmol) was then added thereto. The temperature of the reactionmixture was gradually elevated to room temperature, at which stirringwas performed for 16 hours. Water was added to the reaction mixture,followed by extraction with ethyl acetate. The organic layer was washedwith brine and then dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was subjected to flash chromatography on a silica gel column.The fraction obtained from the hexane:ethyl acetate (=2:1) eluate wasconcentrated under reduced pressure to give the title compound (76 mg,63%) as a white solid. The resulting solid was washed with hexane-etherand then collected by filtration, whereby the title compound wasobtained as a white powder.

Melting point: 109-111° C.

IR (ATR) V: 2933, 2859, 1596, 1575, 1558, 1473, 1415, 1392, 1322, 1280,1238, 1209, 1172, 1145, 1083, 1010, 991, 970, 885, 844, 821, 767, 754,730, 703, 667, 630, 599, 565, 520, 466, 410 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.84 (3H, t, J=7.3 Hz), 1.09-1.40 (4H, m),2.07-2.10 (1H, m), 2.37-2.49 (1H, m), 3.98 (1H, dd, J=11.6, 3.5 Hz),7.06 (1H, d, J=6.1 Hz), 7.39 (2H, d, J=8.8 Hz), 7.48 (2H, d, J=8.6 Hz),8.53 (2H, d, J=6.1 Hz).

MS (m/z): 324 (M⁺+H).

Elemental Analysis for C₁₆H₁₈ClNO₂S

Calculated: C, 59.34%; H, 5.60%; Cl, 10.95%; N, 4.33%; S, 9.90%.

Found: C, 59.41%; H, 5.54%; Cl, 11.18%; N, 4.47%; S, 10.09%.

Example 121 4-[(4-Chlorophenylsulfonyl)(cyclopentyl)methyl]pyridine

A toluene (5 ml) solution of the4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained inExample 119, cyclopentanol (49 μl, 0.538 mmol) andcyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heatedunder reflux for 3 days under an argon atmosphere. After cooling to roomtemperature, the reaction mixture was added with cyclopentanol (49 μl,0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538mol). The mixture was heated under reflux for 22 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate (=2:1) eluate was concentrated under reducedpressure to give the title compound (77 mg, 88%) as a white solid. Theresulting solid was washed with hexane-ether and collected byfiltration, whereby the title compound was obtained as a white powder.

Melting point: 133-135° C.

IR (ATR) ν: 2960, 2867, 1594, 1577, 1558, 1473, 1415, 1392, 1342, 1319,1278, 1224, 1143, 1083, 1010, 993, 954, 902, 840, 821, 767, 750, 705,642, 592, 551, 507, 464 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92-1.08 (1H, m), 1.44-1.83 (6H, m),2.33-2.45 (1H, m), 2.78-2.90 (1H, m), 3.88 (1H, d, J=10.3 Hz), 7.03 (2H,d, J=5.1 Hz), 7.32 (2H, d, J=8.6 Hz), 7.43 (2H, d, J=8.6 Hz), 8.46 (2H,d, J=5.6 Hz).

MS (m/z): 336 (M⁺+H).

Elemental Analysis for C₁₇H₁₈ClNO₂S

Calculated: C, 60.80%; H, 5.40%; Cl, 10.56%; N, 4.17%; S, 9.55%.

Found: C, 60.76%; H, 5.44%; Cl, 10.68%; N, 4.20%; S, 9.61%.

Example 1224-[(4-Chlorophenylsulfonyl)(tetrahydropyran-4-yl)methyl]pyridine

A toluene (5 ml) solution of the4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained inExample 119, tetrahydropyran-4-ol (51 μl, 0.538 mmol) andcyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heatedunder reflux for 3 days under an argon atmosphere. After cooling to roomtemperature, the reaction mixture was added with tetrahydropyran-4-ol(51 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg,0.538 mol), followed by heating under reflux for 22 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate (=1:2) eluate was concentrated under reducedpressure to give the title compound (65 mg, 71%) as a white solid. Theresulting solid was washed with hexane-ether and collected byfiltration, whereby the title compound was obtained as a white powder.

Melting point: 208-209° C.

IR (ATR) ν: 2846, 1594, 1573, 1560, 1475, 1440, 1417, 1394, 1371, 1315,1278, 1245, 1211, 1180, 1143, 1083, 989, 877, 835, 773, 752, 703, 630,603, 565, 524, 478, 451 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.22-1.42 (2H, m), 1.60-1.75 (1H, m),2.30-2.40 (1H, m), 2.78-3.01 (1H, m), 3.41 (1H, td, J=11.7, 2.4 Hz),3.51 (1H, td, J=11.9, 2.0 Hz), 3.80-3.93 (1H, m), 3.87 (1H, d, J=8.6Hz), 3.98-4.06 (1H, m), 7.00-7.12 (2H, m), 7.30 (2H, d, J=8.8 Hz), 7.43(2H, d, J=8.6 Hz), 8.47 (2H, d, J=5.4 Hz).

MS (m/z): 352 (M⁺+H).

Example 1234-[(1-Benzylpiperidin-4-yl)(4-chlorophenylsulfonyl)methyl]pyridine

A toluene (5 ml) solution of the4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained inExample 119, 1-benzylpiperidin-4-ol (103 mg, 0.538 mmol) andcyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heatedunder reflux for 3 days under an argon atmosphere. After cooling to roomtemperature, the reaction mixture was added with 1-benzylpiperidin-4-ol(103 mg, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg,0.538 mol), followed by heating under reflux for 22 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column. The fraction obtained from themethanol:methylene chloride (=1:10) eluate was concentrated underreduced pressure. The residue thus obtained was purified by highperformance liquid chromatography (using a mixed solvent ofwater/acetonitrile/formic acid), whereby the title compound (40 mg, 35%)was obtained as an amorphous substance.

IR (ATR) ν: 2938, 2803, 2763, 1594, 1560, 1475, 1452, 1415, 1367, 1317,1280, 1218, 1176, 1143, 1085, 1012, 975, 825, 750, 742, 698, 617, 566,536, 464 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.21-1.37 (2H, m), 1.49-1.70 (1H, m),1.92-2.01 (1H, m), 2.03-2.14 (1H, m), 2.25-2.35 (1H, m), 2.52-2.65 (1H,m), 2.79-2.85 (1H, m), 2.90-3.00 (1H, m), 3.47 (2H, s), 3.86 (1H, d,J=8.1 Hz), 7.02-7.12 (2H, m), 7.20-7.38 (7H, m), 7.43 (2H, d, J=8.5 Hz),8.45 (2H, d, J=5.4 Hz).

MS (m/z): 441 (M⁺+H).

HRMS (FAB): as C₂₄H₂₆O₂N₂ClS (M⁺+H)

Calculated: 441.1404

Found: 441.1387

Example 1244-[(4-Chlorophenylsulfonyl)(1-methylpiperidin-4-yl)methyl]pyridine

A toluene (5 ml) solution of the4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained inExample 119, 1-methylpiperidin-4-ol (62 μl, 0.538 mmol) andcyanomethylenetri-n-butylphosphorane (62 μl, 0.538 mol) was heated underreflux for 3 days under an argon atmosphere. After cooling to roomtemperature, the reaction mixture was added with 1-methylpiperidin-4-ol(62 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg,0.538 mol), followed by heating under reflux for 22 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography, and the fraction obtained from themethanol:methylene chloride (=1:50) eluate was concentrated underreduced pressure. The residue thus obtained was purified by highperformance liquid chromatography (using a mixed solvent ofwater/acetonitrile/formic acid) to give the title compound (31 mg, 33%)as a white solid. The resulting solid was washed with hexane-ether andthen, collected by filtration, whereby the title compound was obtainedas a white powder.

Melting point: 176-177° C.

IR (ATR) ν: 3077, 2935, 2856, 2786, 2740, 1594, 1556, 1465, 1450, 1413,1380, 1346, 1315, 1280, 1241, 1145, 1085, 1008, 973, 850, 835, 798, 750,705, 617, 561, 528, 476, 464, 424 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.22-1.38 (2H, m), 1.50-1.68 (1H, m),1.88-1.99 (1H, m), 2.00-2.10 (1H, m), 2.25 (3H, s), 2.30-2.40 (1H, m),2.50-2.63 (1H, m), 2.74-2.83 (1H, m), 2.89-2.95 (1H, m), 3.86 (1H, d,J=8.3 Hz), 7.08 (2H, d, J=4.6 Hz), 7.30 (2H, d, J=8.6 Hz), 7.44 (2H, d,J=8.6 Hz), 8.46 (2H, d, J=5.6 Hz).

MS (m/z): 365 (M⁺+H).

Elemental Analysis for C₁₈H₂₁ClN₂O₂S

Calculated: C, 59.25%; H, 5.80%; Cl, 9.72%; N, 7.68%; S, 8.79%.

Found: C, 59.00%; H, 5.76%; Cl, 9.75%; N, 7.61%; S, 8.77%.

Example 1254-(4-Chlorophenylsulfonyl)-N,N-dimethyl-4-(pyridin-4-yl)butylamine

A toluene (5 ml) solution of the4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained inExample 119, 3-dimethylamino-1-propanol (62 μl, 0.538 mmol) andcyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heatedunder reflux for 3 days under an argon atmosphere. After cooling to roomtemperature, the reaction mixture was added with3-dimethylamino-propan-1-ol (62 μl, 0.538 mmol) andcyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol), followed byheating under reflux for 22 hours under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue was subjected to chromatography on asilica gel column, and the fraction obtained from the methanol:methylenechloride (=1:10) eluate was concentrated under reduced pressure. Theresidue thus obtained was purified by high performance liquidchromatography (using a mixed solvent of water/acetonitrile/formic acid)to give the title compound (44 mg, 48%) as a white solid. The resultingsolid was washed with hexane-ether and then, collected by filtration,whereby the title compound was obtained as a white powder.

Melting point: 78-80° C.

IR (ATR) ν: 3089, 2985, 2937, 2809, 2757, 2596, 1587, 1455, 1413, 1392,1322, 1278, 1203, 1145, 1083, 1041, 1010, 991, 962, 846, 821, 767, 754,703, 628, 578, 539, 514, 472 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 1.38-1.43 (2H, m), 2.05-2.29 (3H, m), 2.11(6H, s), 2.39-2.50 (1H, m), 4.05-4.13 (1H, m), 7.07 (2H, d, J=6.1 Hz),7.40 (2H, d, J=8.5 Hz), 7.48 (2H, d, J=8.6 Hz), 8.53 (2H, d, J=6.1 Hz).

MS (m/z): 353 (M⁺+H).

Elemental Analysis for C₁₇H₂₁ClN₂O₂S

Calculated: C, 57.86%; H, 6.00%; Cl, 10.05%; N, 7.94%; S, 9.09%.

Found: C, 57.62%; H, 5.92%; Cl, 9.89%; N, 7.91%; S, 9.12%.

Example 1263-(4-Chlorophenylsulfonyl)-N,N-dimethyl-3-(pyridin-4-yl)propylamine

A toluene (5 ml) solution of the4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained inExample 119, 2-dimethylaminoethanol (54 μl, 0.538 mmol) andcyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heatedunder reflux for 3 days under an argon atmosphere. After cooling to roomtemperature, the reaction mixture was added with 2-dimethylaminoethanol(54 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg,0.538 mol), followed by heating under reflux for 22 hours under an argonatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected tochromatography on a silica gel column, and the fraction obtained fromthe methanol:methylene chloride (=1:10) eluate was concentrated underreduced pressure. The residue thus obtained was purified by highperformance liquid chromatography (using a mixed solvent ofwater/acetonitrile/formic acid) to give the title compound (49 mg, 55%)as a white solid. The resulting solid was washed with hexane-ether andthen, collected by filtration, whereby the title compound was obtainedas a white powder.

Melting point: 91-92° C.

IR (ATR) ν: 3031, 2975, 2940, 2857, 2821, 2790, 1587, 1575, 1554, 1459,1413, 1384, 1313, 1280, 1249, 1143, 1083, 1045, 1008, 991, 842, 821,759, 723, 703, 630, 570, 526, 468 cm⁻¹.

¹H-NMR (400 MHz, CDCl₃) δ: 2.05-2.20 (2H, m), 2.11 (6H, s), 2.59-2.70(1H, m), 4.35 (1H, dd, J=10.5, 3.2 Hz), 7.11 (2H, d, J=6.1 Hz), 7.39(2H, d, J=8.6 Hz), 7.59 (2H, d, J=8.6 Hz), 8.53 (2H, d, J=6.1 Hz).

MS (m/z): 339 (M⁺+H).

Elemental Analysis for C₁₆H₁₉ClN₂O₂S

Calculated: C, 56.71%; H, 5.65%; Cl, 10.46%; N, 8.27%; S, 9.46%.

Found: C, 56.64%; H, 5.61%; Cl, 10.51%; N, 8.26%; S, 9.57%.

Referential Example 13 2-[(2,5-Difluorophenyl)-hydroxymethyl]pyridine

Under an argon atmosphere, n-butyl lithium (3.92 ml, 6 mmol) was addeddropwise to a tetrahydrofuran (10 ml) solution of 2-bromopyridine (572μl, 6 mmol) at −78° C. and the mixture was stirred for 30 minutes. Tothe resulting brown solution, 2,5-difluorobenzaldehyde (655 μl, 6 mmol)was added dropwise and the temperature of the mixture was graduallyraised to room temperature. Water was added to the reaction mixture,followed by extraction with ethyl acetate. After drying the solvent, theresidue obtained by concentration under reduced pressure was purified bysilica gel chromatography, whereby the title compound (120 mg, 9%) wasobtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 5.45 (1H, br), 6.08 (1H, s), 6.87-7.15 (3H,m), 7.2-7.3 (2H, m), 7.65 (1H, m), 8.56 (1H, m).

mp: 65-66° C.

Referential Example 142-[Chloro-(2,5-difluorophenyl)methyl]-3-methylpyridine hydrochloride

Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol)of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran(2.0 ml) solution of 2-bromo-3-methylpyridine (510 mg, 3 mmol) under icecooling and the mixture was stirred at room temperature for 60 minutes.Under ice cooling, 2,5-difluorobenzaldehyde (328 μl, 3 mmol) was addeddropwise to the resulting brown solution. The temperature of thereaction mixture was then raised gradually to room temperature. Afteraddition of a saturated aqueous solution of ammonium chloride, theresulting mixture was extracted with ethyl acetate. After drying thesolvent, the residue obtained by concentration under reduced pressurewas purified by silica gel chromatography (hexane:ethyl acetate-8:1) toyield a mixture containing the title compound. To the resulting mixturewere added thionyl chloride (2.0 ml) and a drop of dimethylformamide,followed by stirring at room temperature for 14 hours. Distillation ofexcess thionyl chloride under reduced pressure yielded a whiteprecipitate. The resulting white precipitate was triturated with hexaneand diethyl ether, whereby the title compound (101 mg, 12%) wasobtained.

¹H-NMR (400 MHz, CDCl₃) δ: 2.37 (3H, s), 6.95-7.10 (2H, m), 7.28 (1H,s), 7.7-7.8 (2H, m), 8.11 (1H, d, J=6.3 Hz), 8.72 (1H, d, J=4.9 Hz).

IR (ATR) cm⁻¹: 1612, 1496, 1294, 1232, 821.

mp: 118-119° C.

MS m/z: 254 (M⁺+H).

Referential Example 152-[(2,5-Difluorophenyl)-hydroxymethyl]-5-methylpyridine

Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol)of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran(2 ml) solution of 2-bromo-5-methylpyridine (510 mg, 3 mmol) under icecooling and the mixture was stirred at room temperature for 60 minutes.Under ice cooling, 2,5-difluorobenzaldehyde (328 μl, 3 mmol) was addeddropwise to the resulting brown solution. The temperature of thereaction mixture was raised gradually to room temperature. A saturatedaqueous solution of ammonium chloride was added and the mixture wasextracted with ethyl acetate. After drying the solvent, the residueobtained by concentration under reduced pressure was purified by silicagel chromatography (hexane:ethyl acetate=5:1), whereby the titlecompound (130 mg, 18%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 2.31 (3H, s), 5.38 (1H, br), 6.04 (1H, s),6.83-7.18 (4H, m), 7.44 (1H, dd, J=2.0, 8.0 Hz), 8.37 (1H, m).

IR (ATR) cm⁻¹: 1485, 1178, 1132, 814.

MS m/z: 236 (M⁺+H).

Referential Example 162-[(2,5-Difluorophenyl)-hydroxymethyl]-4-methylpyridine

Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol)of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran(2 ml) solution of 2-bromo-4-methylpyridine (334 μl, 3 mmol) under icecooling and the mixture was stirred at room temperature for 60 minutes.Under ice cooling, 2,5-difluorobenzaldehyde (328 μl, 3 mmol) was addeddropwise to the resulting brown solution. The temperature of thereaction mixture was raised gradually to room temperature. To thereaction mixture was added a saturated aqueous solution of ammoniumchloride, followed by extraction with ethyl acetate. After drying thesolvent, the residue obtained by concentration under reduced pressurewas purified by silica gel chromatography (hexane:ethyl acetate=5:1),whereby the title compound (456 mg, 65%) was obtained as needlecrystals.

¹H-NMR (400 MHz, CDCl₃) δ: 2.30 (3H, s), 5.48 (1H, br-s), 6.02 (1H, s),6.83-7.13 (5H, m), 8.38 (1H, m).

IR (ATR) cm⁻¹: 3162, 1610, 1481, 1054, 825.

mp: 105-106° C.

MS m/z: 236 (M⁺+H).

Referential Example 17 2-Bromo-3-methoxypyridine

Under a nitrogen atmosphere, sodium hydride (605 mg, 15.1 mmol) wasadded in portions to methanol (10 ml) under ice cooling. Twenty minuteslater, a dimethylformamide (20 ml) solution of 2-bromo-3-hydroxypyridine(2.5 g, 14.4 mmol) was added to the resulting mixture. The reactionmixture was distilled under reduced pressure to remove methanol and tothe residue was added methyl iodide (0.94 ml, 15.1 mmol). The mixturewas stirred at room temperature for 3 hours.

After the reaction mixture was concentrated to dryness, water (50 ml)and ether (50 ml) were added to the residue. The organic layer obtainedby separation was washed with a saturated aqueous solution of sodiumbicarbonate and brine. The extract was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue was thenpurified by silica gel chromatography (hexane:ethyl acetate=8:1),whereby the title compound (1.51 g, 56%) was obtained as colorlessneedle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 3.90 (3H, s), 7.12 (1H, m), 7.21 (1H, dd,J=4.8, 8.0 Hz), 7.97 (1H, m).

IR (ATR) cm⁻¹: 1556, 1410, 1076, 1049, 788.

mp: 34° C.

Referential Example 18 3-Allyloxy-2-bromopyridine

In a similar manner to that employed for the synthesis of2-bromo-3-methoxypyridine, the title compound (2.35 g, 76%) was obtainedas an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 4.62 (2H, m), 5.33 (1H, dd, J=1.2, 10.4 Hz),5.47 (1H, dd, J=1.2, 17.6 Hz), 6.06 (1H, m), 7.11 (1H, dd, J=1.2 Hz, 8.0Hz), 7.18 (1H, dd, J=4.8, 8.0 Hz), 7.98 (1H, m).

IR (ATR) cm⁻¹: 1562, 1408, 1282, 1052, 790.

MS m/z: 215 (M⁺+H).

Referential Example 192-[(2,5-Difluorophenyl)-hydroxymethyl]-3-methoxypyridine

Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol)of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran(2 ml) solution of 2-bromo-3-methoxypyridine (564 mg, 3 mmol) under icecooling. The resulting mixture was stirred at room temperature for 60minutes. Under ice cooling, 2,5-difluorobenzaldehyde (328 μl, 3 mmol)was added dropwise to the resulting brown solution. The temperature ofthe reaction mixture was raised gradually to room temperature. To thereaction mixture was added a saturated aqueous solution of ammoniumchloride, followed by extraction with ethyl acetate. The solvent wasdried, followed by concentration under reduced pressure to yield needlecrystals. The resulting needle crystals were triturated with hexane,whereby the title compound (660 mg, 88%) was obtained.

¹H-NMR (400 MHz, CDCl₃) δ: 3.71 (3H, s), 5.56 (1H, br, J=6.0 Hz), 6.16(1H, d, J=6.0 Hz), 6.75-7.00 (3H, m), 7.14 (1H, m), 7.26 (1H, m), 8.18(1H, m).

IR (ATR) cm⁻¹: 3384, 1577, 1488, 1284, 810.

mp: 94-95° C.

MS m/z: 252 (M⁺+H).

Referential Example 203-Allyloxy-2-[(2,5-difluorophenyl)-hydroxymethyl]pyridine

Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol)of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran(2 ml) solution of 3-allyloxy-2-bromopyridine (642 mg, 3 mmol) under icecooling. The resulting mixture was stirred at room temperature for 60minutes. Under ice cooling, 2,5-difluorobenzaldehyde (328 μl, 3 mmol)was added dropwise to the resulting brown solution. The temperature ofthe reaction mixture was raised gradually to room temperature. Asaturated aqueous solution of ammonium chloride was added and then, themixture was extracted with ethyl acetate. The solvent was dried,followed by concentration under reduced pressure. The residue thusobtained was purified by silica gel chromatography (hexane:ethylacetate=4:1), whereby the title compound (375 mg, 45%) was obtained asan oil.

¹H-NMR (400 MHz, CDCl₃) δ: 4.38 (1H, m), 4.44 (1H, m), 5.16 (1H, m),5.18 (1H, m), 5.61 (1H, br, J=6.4 Hz), 5.78 (1H, m), 6.17 (1H, d, J=6.0Hz), 6.73-6.96 (3H, m), 7.10 (1H, m), 7.22 (1H, m), 8.19 (1H, m).

IR (ATR) cm⁻¹: 3367, 1575, 1490, 1276, 1180, 795.

MS m/z: 278 (M⁺+H).

Referential Example 21 3-[(2,5-difluorophenyl)-hydroxymethyl]pyridine

Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol)of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran(2 ml) solution of 3-bromopyridine (286 μl, 3 mmol) under ice cooling.The resulting mixture was stirred at room temperature for 60 minutes.Under ice cooling, 2,5-difluorobenzaldehyde (328 μl, 3 mmol) was addeddropwise to the resulting brown solution. The temperature of thereaction mixture was raised gradually to room temperature. To thereaction mixture was added a saturated aqueous solution of ammoniumchloride and then, the mixture was extracted with ethyl acetate. Thesolvent was dried, followed by concentration under reduced pressure. Theresidue thus obtained was purified by silica gel chromatography(hexane:ethyl acetate=1:1), whereby the title compound (296 mg, 45%) wasobtained as needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 3.76 (1H, br), 6.10 (1H, s), 6.88-6.98 (2H,m), 7.20-7.30 (2H, m), 7.70 (1H, m), 8.42 (1H, d, J=4.8 Hz), 8.53 (1H,m).

IR (ATR) cm⁻¹: 1486, 1429, 1178, 1130, 739, 707.

mp: 79-80° C.

Referential Example 22 4-[(2,5-Difluorophenyl)-hydroxymethyl]pyridine

In a similar manner to Referential Example 21 except for the use of4-bromopyridine, the title compound (79 mg, 8%) was obtained as needlecrystals.

¹H-NMR (400 MHz, CDCl₃) δ: 6.08 (1H, s), 6.90-7.00 (2H, m), 7.15 (1H,m), 7.32 (1H, dd, J=1.6, 8.4 Hz), 8.48 (1H, dd, J=11.6, 8.4 Hz).

IR (ATR) cm⁻¹: 1602, 1489, 1415, 1174, 1049, 711.

mp: 120-121° C.

MS m/z: 221 (M⁺)

Referential Example 23 5-[(2,5-Difluorophenyl)-hydroxymethyl]pyrimidine

In a similar manner to Referential Example 21 except for the use of5-bromopyrimidine, the title compound (117 mg, 18%) was obtained as anoil.

¹H-NMR (400 MHz, CDCl₃) δ: 6.12 (1H, s), 6.90-7.02 (2H, m), 7.26 (1H,m), 8.70 (2H, s), 9.04 (1H, s).

IR (ATR) cm⁻¹: 3219, 1566, 1489, 1408, 1180, 715.

MS m/z: 205 (M⁺-OH)

Example 1272-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyridine

The 2-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (88 mg, 0.40 mmol)obtained in Referential Example 13 was dissolved in thionyl chloride(2.0 ml). To the resulting solution was added a catalytic amount ofdimethylformamide, followed by stirring for 15 hours.

The reaction mixture was concentrated under reduced pressure. To theresidue was added dioxane and the mixture was concentrated further. Theresidue was dissolved in dimethylformamide (5 ml), followed by theaddition of 4-chlorobenzenethiol (79 mg, 0.55 mmol) and potassiumcarbonate (226 mg, 1.64 mmol) under a nitrogen atmosphere. The resultingmixture was stirred at 50° C. for 1 hour. After cooling to roomtemperature, diethyl ether (50 ml) was added to the reaction mixture.The mixture was washed with water and brine. The organic layer was driedover magnesium sulfate and concentrated under reduced pressure. Theresidue was subjected to silica gel chromatography (hexane:ethylacetate=10:1), whereby the title compound (128 mg, 92%) was obtained asan oil.

¹H-NMR (400 MHz, CDCl₃) δ: 5.89 (1H, s), 6.80-7.27 (7H, m), 7.38 (1H, d,J=7.6 Hz), 7.48 (1H, m), 7.65 (1H, m), 8.63 (1H, m).

IR (ATR) cm⁻¹: 1585, 1488, 1432, 1093, 810.

MS m/z: 348 (M⁺+H).

Example 1282-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-3-methylpyridine

To a dimethylformamide (5 ml) solution of the2-[chloro-(2,5-difluorophenyl)methyl]-3-methylpyridine hydrochloride (94mg, 0.32 mmol) obtained in Referential Example 14 were added4-chlorobenzenethiol (70 mg, 0.49 mmol) and potassium carbonate (265 mg,1.92 mmol) under a nitrogen atmosphere. The resulting mixture wasstirred at 50° C. for 1 hour. After cooling to room temperature, diethylether (50 ml) was added to the reaction mixture. The resulting mixturewas washed with water and brine. The organic layer was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas subjected to silica gel chromatography (hexane:ethyl acetate=10:1),whereby the title compound (103 mg, 89%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 2.21 (3H, s), 5.87 (1H, s), 6.77 (1H, m),7.00-7.19 (5H, m), 7.36 (1H, m), 7.45 (1H, m), 8.45 (1H, dd, J=1.2, 4.8Hz).

IR (ATR) cm⁻¹: 1572, 1489, 1093, 810.

MS m/z: 362 (M⁺+H).

Example 1292-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-5-methylpyridine

The 2-[(2,5-difluorophenyl)-hydroxymethyl]-5-methylpyridine (125 mg,0.53 mmol) obtained in Referential Example 15 was dissolved in thionylchloride (1.0 ml). To the resulting solution was added a catalyticamount of dimethylformamide and the mixture was stirred for 14 hours.

The reaction mixture was concentrated under reduced pressure. Dioxanewas added to the residue and the mixture was concentrated further. Theresulting residue was dissolved in dimethylformamide (5 ml), followed bythe addition of 4-chlorobenzenethiol (115 mg, 0.80 mmol) and potassiumcarbonate (438 mg, 3.18 mmol) under a nitrogen atmosphere. The mixturewas stirred at 50° C. for 1 hour. After cooling to room temperature,diethyl ether (50 ml) was added to the reaction mixture. The mixture waswashed with water and brine. The organic layer was dried over magnesiumsulfate and concentrated under reduced pressure. The residue wassubjected to silica gel chromatography (hexane:ethyl acetate=10:1),whereby the title compound (120 mg, 66%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 2.29 (3H, s), 5.83 (1H, s), 6.80-6.93 (2H,m), 7.16 (2H, m), 7.20 (2H, m), 7.28 (1H, m), 7.43 (1H, m), 8.41 (1H, d,J=0.8 Hz).

IR (ATR) cm⁻¹: 1475, 1095, 814.

MS m/z: 362 (M⁺+H).

Example 1302-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-4-methylpyridine

The 2-[(2,5-difluorophenyl)-hydroxymethyl]-4-methylpyridine (235 mg,0.53 mmol) obtained in Referential Example 16 was dissolved in thionylchloride (2.0 ml). To the resulting solution was added a catalyticamount of dimethylformamide and the mixture was stirred for 16 hours.The reaction mixture was concentrated under reduced pressure. Dioxanewas added to the residue and the mixture was concentrated further.

The residue was dissolved in dimethylformamide (10 ml), followed by theaddition of 4-chlorobenzenethiol (217 mg, 1.5 mmol) and potassiumcarbonate (828 mg, 6.0 mmol) under a nitrogen atmosphere. The mixturewas stirred at 50° C. for 1 hour. After cooling to room temperature,diethyl ether (50 ml) was added and the mixture was washed with waterand brine. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was subjected to silicagel chromatography (hexane:ethyl acetate=10:1), whereby the titlecompound (290 mg, 80%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 2.31 (3H, s), 5.82 (1H, s), 6.80-7.0 (3H, m),7.15 (2H, d, J=8.8 Hz), 7.16 (1H, m), 7.21 (2H, d, J=8.8 Hz), 7.45 (1H,m), 8.45 (1H, d, J=5.6 Hz).

IR (ATR) cm⁻¹: 1600, 1489, 1475, 1093, 812.

MS m/z: 362 (M⁺+H).

Example 1312-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-3-methoxypyridine

The 2-[(2,5-difluorophenyl)-hydroxymethyl]-3-methoxypyridine (251 mg,1.0 mmol) obtained in Referential Example 19 was dissolved in thionylchloride (2.0 ml). To the resulting solution was added a catalyticamount of dimethylformamide and the mixture was stirred for 16 hours.

The reaction mixture was concentrated under reduced pressure. Dioxanewas added to the residue and the mixture was concentrated further.

The residue was dissolved in dimethylformamide (10 ml), followed by theaddition of 4-chlorobenzenethiol (289 mg, 2.0 mmol) and potassiumcarbonate (1.10 g, 8.0 mmol) under a nitrogen atmosphere. The resultingmixture was stirred at 50° C. for 1 hour. After cooling to roomtemperature, diethyl ether (50 ml) was added, and the mixture was washedwith water and brine. The organic layer was dried over magnesium sulfateand concentrated under reduced pressure. The residue was subjected tosilica gel chromatography (hexane:ethyl acetate=10:1), whereby the titlecompound (256 mg, 58%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 3.77 (3H, s), 6.25 (1H, s), 6.82 (2H, m),7.15 (2H, d, J=8.4 Hz), 7.10-7.20 (2H, m), 7.25 (2H, d, J=8.8 Hz), 7.52(1H, m), 8.24 (1H, m).

IR (ATR) cm⁻¹: 1489, 1423, 1273, 1091, 831.

MS m/z: 378 (M⁺+H).

Example 1323-Allyloxy-2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyridine

The 3-allyloxy-2-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (370 mg,1.33 mmol) obtained in Referential Example 20 was dissolved in thionylchloride (2.0 ml). To the resulting solution was added a catalyticamount of dimethylformamide and the mixture was stirred for 16 hours.

The reaction mixture was concentrated under reduced pressure. Dioxanewas added to the residue and the mixture was concentrated further.

The residue was dissolved in dimethylformamide (10 ml), followed by theaddition of 4-chlorobenzenethiol (217 mg, 1.5 mmol) and potassiumcarbonate (828 mg, 6.0 mmol) under a nitrogen atmosphere. The mixturewas stirred at 50° C. for 1 hour. After cooling to room temperature,diethyl ether (50 ml) was added, and the mixture was washed with waterand brine. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was subjected to silicagel chromatography (hexane:ethyl acetate=10:1), whereby the titlecompound (256 mg, 68%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 4.46 (2H, m), 5.24 (1H, d, J=10.6 Hz), 5.28(1H, d, J=17.2 Hz), 5.90 (1H, m), 6.29 (1H, d, J=1.2 Hz), 6.82 (2H, m),7.15 (2H, d, J=8.4 Hz), 7.06-7.20 (2H, m), 7.24 (2H, d, J=8.4 Hz), 7.50(1H, m), 8.24 (1H, m).

IR (ATR) cm⁻¹: 1572, 1489, 1438, 1276, 1093, 814.

MS m/z: 404 (M⁺+H).

Example 1333-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyridine

The 3-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (87 mg, 0.39 mmol)obtained in Referential Example 21 was dissolved in thionyl chloride(1.0 ml). To the resulting solution was added a catalytic amount ofdimethylformamide and the mixture was stirred for 14 hours.

The reaction mixture was concentrated under reduced pressure. Dioxanewas added to the residue and the mixture was concentrated further.

The residue thus obtained was dissolved in dimethylformamide (5 ml),followed by the addition of 4-chlorobenzenethiol (84 mg, 0.58 mmol) andpotassium carbonate (323 mg, 2.34 mmol) under a nitrogen atmosphere. Themixture was stirred at 50° C. for 1 hour. After cooling to roomtemperature, diethyl ether (50 ml) was added, and the mixture was washedwith water and brine. The organic layer was dried over magnesium sulfateand concentrated under reduced pressure. The residue was subjected tosilica gel chromatography (hexane:ethyl acetate=1:1), whereby the titlecompound (131 mg, 96%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 5.73 (1H, s), 6.84-6.96 (2H, m), 7.18 (2H,m), 7.19 (2H, m), 7.15-7.22 (2H, m), 7.71 (1H, m), 8.49 (1H, dd, J=1.6,4.8 Hz), 8.58 (1H, d, J=2.0 Hz).

IR (ATR) cm⁻¹: 1489, 1093, 814, 710.

MS m/z: 348 (M⁺+H).

Example 1345-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyrimidine

The 5-[(2,5-difluorophenyl)-hydroxymethyl]pyrimidine (111 mg, 0.5 mmol)obtained in Referential Example 23 was dissolved in thionyl chloride(1.0 ml). To the resulting solution was added a catalytic amount ofdimethylformamide and the mixture was stirred for 16 hours.

The reaction mixture was concentrated under reduced pressure. Dioxanewas added to the residue and the mixture was concentrated further.

The residue was dissolved in dimethylformamide (5 ml), followed by theaddition of 4-chlorobenzenethiol (108 mg, 0.75 mmol) and potassiumcarbonate (414 mg, 3.0 mmol) under a nitrogen atmosphere. The mixturewas stirred at 50° C. for 1 hour. After cooling to room temperature,diethyl ether (50 ml) was added, and the mixture was washed with waterand brine. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was subjected to silicagel chromatography (hexane:ethyl acetate=4:1), whereby a mixture (202mg) of the title compound and an unidentified compound was obtained asan oil.

¹H-NMR (400 MHz, CDCl₃) δ: 5.66 (1H, s), 6.96 (2H, m), 7.17-7.34 (5H,d), 8.70 (2H, s), 9.09 (1H, s).

MS m/z: 349 (M⁺+H).

Example 1352-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]pyridine

To a methanol (12 ml) solution of the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyridine (120 mg,0.345 mmol) obtained in Example 127 was added hexaammoniumheptamolybdate tetrahydrate (80 mg), followed by the addition of 30%aqueous hydrogen peroxide (6 ml). The resulting mixture was stirred for24 hours. The precipitate thus obtained was collected by filtration andrecrystallized from ethanol, whereby the title compound (96 mg, 73%) wasobtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 5.93 (1H, s), 6.87-7.00 (2H, m), 7.28 (1H,m), 7.37 (2H, d, J=8.8 Hz), 7.53 (2H, d, J=8.8 Hz), 7.60 (1H, d, J=8.0Hz), 7.71 (1H, m), 8.00 (1H, m), 8.59 (1H, m).

IR (ATR) cm⁻¹: 1585, 1484, 1434, 1321, 1147, 817. Mp: 171-172° C.

MS m/z: 380 (M⁺+H)

Anal. calcd for C₁₈H₁₂ClF₂NO₂S: C, 56.92%; H, 3.18%; N, 3.69%; S, 8.44%;Cl, 9.33%; F, 10.00%. Found: C, 56.76%; H, 3.19%; N, 3.77%; S, 8.55%;Cl, 9.27%; F, 10.02%.

Fab-MS: 380.0309 (Calcd for C₁₈H₁₃ClF₂NO₂S: 380.0324).

Example 1362-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-3-methylpyridine

In a similar manner to Example 135, the title compound (35 mg, 35%) wasobtained as colorless needle crystals by using the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-3-methylpyridineobtained in Example 128 and purifying by silica gel chromatography(hexane:ethyl acetate=5:1).

¹H-NMR (400 MHz, CDCl₃) δ: 2.36 (3H, s), 6.18 (1H, s), 6.89-7.02 (2H,m), 7.17 (1H, m), 7.37 (2H, d, J=8.4 Hz), 7.46 (1H, d, J=7.2 Hz), 7.53(2H, d, J=8.4 Hz), 8.06 (1H, m), 8.53 (1H, d, J=4.0 Hz).

IR (ATR) cm⁻¹: 1571, 1477, 1321, 1151, 1080, 816.

mp: 142-143° C.

MS m/z: 394 (M⁺+H).

Anal. calcd for C₁₉H₁₄ClF₂NO₂S: C, 57.94%; H, 3.58%; N, 3.56%; S, 8.12%;Cl, 9.00%; F, 9.65%. Found: C, 58.03%; H, 3.66%; N, 3.78%; S, 8.12%; Cl,9.13%; F, 9.59%.

Example 1372-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-5-methylpyridine

In a similar manner to Example 135 except for the use of the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-5-methylpyridineobtained in Example 129, the title compound (91 mg, 73%) was obtained ascolorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 2.33 (3H, s), 5.89 (1H, s), 6.88-7.01 (2H,m), 7.37 (2H, d, J=8.8 Hz), 7.48-7.56 (2H, m), 7.53 (2H, d, J=8.8 Hz),7.99 (1H, m), 8.42 (1H, s).

IR (ATR) cm⁻¹: 1574, 1477, 1319, 1147, 1093, 822.

mp: 159-160° C.

MS m/z: 394 (M⁺+H).

Anal. calcd for C₁₉H₁₄ClF₂NO₂S: C, 57.94%; H, 3.58%; N, 3.56%; S, 8.12%;Cl, 9.00%; F, 9.56%. Found: C, 57.88%; H, 3.61%; N, 3.68%; S, 8.27%; Cl,9.11%; F, 9.70%.

Example 1382-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-4-methylpyridine

In a similar manner to Example 135, the title compound (140 mg, 95%) wasobtained as colorless needle crystals by using the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-4-methylpyridineobtained in Example 130 and purifying by silica gel chromatography(hexane:ethyl acetate=3:1).

¹H-NMR (400 MHz, CDCl₃) δ: 2.36 (3H, s), 5.88 (1H, s), 6.88-7.02 (2H,m), 7.09 (1H, d, J=5.2 Hz), 7.37 (2H, d, J=8.8 Hz), 7.41 (1H, m), 7.52(2H, d, J=8.8 Hz), 7.97 (1H, m), 8.43 (1H, d, J=5.2 Hz).

IR (ATR) cm⁻¹: 1600, 1484, 1322, 1149, 1080, 827.

mp: 116-117° C.

MS m/z: 394 (M⁺+H).

Anal. calcd for C₁₉H₁₄ClF₂NO₂S: C, 57.94%; H, 3.58%; N, 3.56%; S, 8.12%;Cl, 9.00%; F, 9.65%. Found: C, 57.80%; H, 3.66%; N, 3.72%; S, 8.29%; Cl,9.05%; F, 9.71%.

Example 1392-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-3-methoxypyridine

In a similar manner to Example 135, the title compound (71 mg, 87%) wasobtained as colorless columnar crystals by using the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-3-methoxypyridineobtained in Example 131 and recrystallizing from ethanol.

¹H-NMR (400 MHz, CDCl₃) δ: 3.72 (3H, s), 6.62 (1H, s), 6.90-7.04 (2H,m), 7.09 (1H, m), 7.24 (1H, m), 7.35 (2H, d, J=8.8 Hz), 7.53 (2H, d,J=8.8 Hz), 8.18 (1H, m), 8.30 (1H, m).

IR (ATR) cm⁻¹: 1576, 1491, 1429, 1323, 1281, 1147, 796.

mp: 184-185° C.

MS m/z: 410 (M⁺+H).

Anal. calcd for C₁₉H₁₄ClF₂NO₃S: C, 55.68%; H, 3.44%; N, 3.42%; S, 7.82%;Cl, 8.65%; F, 9.27%. Found: C, 55.68%; H, 3.45%; N, 3.60%; S, 7.98%; Cl,8.74%; F, 9.23%.

Example 1403-Allyloxy-2-[[(4-chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]pyridine

In a similar manner to Example 135, the title compound (135 mg, 80%) wasobtained as colorless needle crystals by synthesizing using the3-allyloxy-2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyridineobtained in Example 132 and crystallizing from ethanol.

¹H-NMR (400 MHz, CDCl₃) δ: 4.38 (1H, m), 4.46 (1H, m), 5.29 (1H, dd,J=1.2, 10.4 Hz), 5.35 (1H, dd, J=1.2, 17.2 Hz), 5.93 (1H, m), 6.68 (1H,s), 6.91-7.04 (2H, m), 7.08 (1H, m), 7.22 (1H, dd, J=4.8, 8.4 Hz), 7.34(2H, d, J=8.8 Hz), 7.53 (2H, d, J=8.8 Hz), 8.17 (1H, m), 8.31 (1H, m).

IR (ATR) cm⁻¹: 1577, 1493, 1319, 1151, 822.

mp: 119-120° C.

MS m/z: 436 (M⁺+H).

Anal. calcd for C₂₁H₁₆ClF₂NO₃S: C, 57.87%; H, 3.70%; N, 3.21%; S, 7.36%;Cl, 8.13%; F, 8.72%. Found: C, 57.90%; H, 3.75%; N, 3.37%; S, 7.51%; Cl,8.20%; F, 8.73%.

Example 1413-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]pyridine

In a similar manner to Example 135, the title compound (118 mg, 86%) wasobtained as colorless needle crystals by synthesizing using the3-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyridine obtainedin Example 133 and purifying through silica gel chromatography(hexane:ethyl acetate=4:1).

¹H-NMR (400 MHz, CDCl₃) δ: 5.68 (1H, s), 6.91-7.07 (2H, m), 7.34 (1H,m), 7.40 (2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 7.76 (1H, m), 8.04(1H, m), 8.53 (1H, d, J=2.0 Hz), 8.59 (1H, m).

IR (ATR) cm⁻¹: 1574, 1491, 1421, 1327, 1144, 816.

mp: 130-131° C.

MS m/z: 380 (M⁺+H).

Anal. calcd for C₁₈H₁₂ClF₂NO₂S: C, 56.92%; H, 3.18%; N, 3.69%; S, 8.44%;Cl, 9.33%; F, 10.00%. Found: C, 56.87%; H, 3.16%; N, 3.74%; S, 8.51%;Cl, 9.34%; F, 10.00%.

Example 1424-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]pyridine

The 4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (75 mg, 0.34 mmol)obtained in Referential Example 22 was dissolved in thionyl chloride(1.0 ml). To the resulting solution was added a catalytic amount ofdimethylformamide. The resulting mixture was stirred for 14 hours.

The reaction mixture was concentrated under reduced pressure. Dioxanewas added to the residue and the mixture was concentrated further.

The residue was dissolved in dimethylformamide (5 ml), followed by theaddition of 4-chlorobenzenethiol (74 mg, 0.51 mmol) and potassiumcarbonate (281 mg, 2.04 mmol) under a nitrogen atmosphere. The mixturewas stirred at 50° C. for 1 hour. After cooling to room temperature,diethyl ether (50 ml) was added, and the mixture was washed with waterand brine. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was subjected to silicagel chromatography (hexane:ethyl acetate=1:1), whereby a mixturecontaining the title compound was obtained.

To a methanol (12 ml) solution of the resulting compound was addedhexaammonium heptamolybdate tetrahydrate (60 mg), followed by theaddition of 30% aqueous hydrogen peroxide (6 ml). The resulting mixturewas stirred for 65 hours. Ethyl acetate (80 ml) was added to thereaction mixture. The mixture was washed with water and brine, and thendried over anhydrous magnesium sulfate. The mixture was concentratedunder reduced pressure to remove the solvent. The residue was purifiedby silica gel chromatography (hexane:ethyl acetate=4:1-1:1), whereby thetitle compound (51 mg, 39%) was obtained. The compound wasrecrystallized from ethanol to give colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 5.64 (1H, s), 6.91-7.06 (2H, m), 7.40 (2H, d,J=8.0 Hz), 7.45 (2H, d, J=4.8 Hz), 7.58 (2H, d, J=8.0 Hz), 7.70 (1H, s),8.61 (2H, d, J=4.8 Hz).

IR (ATR) cm⁻¹: 1595, 1493, 1315, 1147, 1082, 823.

mp: 126-127° C.

MS m/z: 380 (M⁺+H).

Anal. calcd for C₁₈H₁₂ClF₂NO₂S: C, 56.92%; H, 3.18%; N, 3.69%; S, 8.44%;Cl, 9.33%; F, 10.00%. Found: C, 56.66%; H, 3.16%; N, 3.83%; S, 8.58%;Cl, 9.32%; F, 9.99%.

Example 1432-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]pyrimidine

In a similar manner to Example 135, the title compound (71 mg, 87%,yield: two steps from the5-[(2,5-difluorophenyl)-hydroxymethyl]pyrimidine of Referential Example23) was obtained as colorless columnar crystals by using the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyrimidine obtainedin Example 134, and purifying through silica gel chromatography(hexane:ethyl acetate=5:1).

¹H-NMR (400 MHz, CDCl₃) δ: 5.65 (1H, s), 6.93-7.10 (2H, m), 7.43 (2H, d,J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz), 7.73 (1H, m), 8.90 (2H, s), 9.21 (1H,s).

IR (ATR) cm⁻¹: 1560, 1490, 1141, 1080, 825.

mp: 136-137° C.

MS m/z: 381 (M⁺+H).

Anal. calcd for C₁₇H₁₁ClF₂N₂O₂S: C, 53.62%; H, 2.91%; N, 7.36%; S,8.42%; Cl, 9.31%; F, 9.98%. Found: C, 53.64%; H, 2.83%; N, 7.44%; S,8.61%; Cl, 9.34%; F, 9.96%.

Example 1443-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-4-hydroxychromen-2-one

At room temperature, glacial acetic acid (60 mg, 1 mmol) and pyridine(80.5 μl, 1 mmol) were added to an ethanol (4 ml) solution of2,5-difluorobenzaldehyde (109 μl, 1 mmol), 4-hydroxycoumarin (162 mg, 1mmol) and 4-chlorothiophenol (144.6 mg, 1 mmol) and the mixture wasstirred for 24 hours. The precipitate thus formed was collected byfiltration and washed with a small amount of ethanol, whereby the titlecompound (345 mg, 80%) was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.16 (1H, s), 6.95-7.12 (3H, m), 7.24-7.27(1H, m), 7.27 (2H, d, J=8.8 Hz), 7.32 (1H, t, J=7.6 Hz), 7.43 (2H, d,J=8.8 Hz), 7.56 (1H, m), 7.94 (1H, dd, J=1.6, 7.6 Hz).

IR (ATR) cm⁻¹: 1668, 1620, 1481, 1194, 818.

mp: 146-147° C.

MS m/z: 431 (M⁺+H).

Example 1453-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-4-methoxychromen-2-one(Compound A) and3-[[(4-chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-2-methoxychromen-4-one(Compound B)

Compound A Compound B

To a benzene-methanol (10:1) solution of3-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-4-hydroxychromen-2-one(118 mg, 0.274 mmol) was added a hexane solution (0.41 ml, 0.822 mmol)of 2N trimethylsilyldiazomethane in portions at room temperature and themixture was stirred for 5 minutes. Acetic acid was added to the reactionmixture until the solution became colorless. The reaction mixture wasthen concentrated under reduced pressure.

The residue was dissolved in methanol (12 ml), followed by the additionof 30% aqueous hydrogen peroxide (6 ml) and hexaammonium heptamolybdatetetrahydrate (60 mg). The resulting mixture was stirred for 20 hours.Ethyl acetate (50 ml) was added to the reaction mixture. The mixture waswashed with water and brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (hexane:ethyl acetate=5:1-3:1) to yield a non polarcompound (22 mg, 17%) as needle crystals, and a polar compound (9.0 mg,7%) as a white solid after solidification with hexane. As a result ofthe NOE (Nuclear Overhauser effect) test, in the nonpolar compound, NOEwas observed between the methoxy and the 5-hydrogen of chromenone. Inthe polar compound, on the other hand, NOE was not observed between themethoxy and the hydrogen on the aromatic ring of the chromenone, but wasobserved between the methoxy and the 6-hydrogen on the difluorobenzenering. The structures of the nonpolar compound and the polar compoundwere therefore determined as3-[[(4-chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-4-methoxychromen-2-one(Compound A) and3-[[(4-chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-2-methoxychromen-4-one(Compound B), respectively.

Compound A

¹H-NMR (400 MHz, CDCl₃) δ: 4.13 (3H, s), 6.39 (1H, s), 6.88 (1H, m),6.98 (1H, m), 7.3-7.4 (2H, m), 7.43 (2H, d, J=8.8 Hz), 7.58 (1H, m),7.70 (2H, d, J=8.8 Hz), 7.73 (1H, m), 8.09 (1H, m).

IR (ATR) cm⁻¹: 1726, 1606, 1493, 1360, 1184, 1085, 768.

mp: 178-179° C.

MS m/z: 477 (M⁺+H).

Anal. calcd for C₂₃H₁₅ClF₂O₃S: C, 57.93%; H, 3.17%; S, 6.72%; Cl, 7.43%;F, 7.97%. Found: C, 57.59%; H, 3.14%; S, 6.85%; Cl, 7.52%; F, 8.01%.

FAB-MS: 477.0393 (Calcd for C₂₃H₁₆ClF₂O₅S: 477.0375).

Compound B

¹H-NMR (400 MHz, CDCl₃) δ: 4.23 (3H, s), 6.54 (1H, s), 6.89 (1H, m),6.96 (1H, m), 7.41 (2H, d, J=8.4 Hz), 7.4-7.46 (2H, m), 7.63 (1H, m),7.73 (2H, d, J=8.4 Hz), 8.02 (1H, m), 8.14 (1H, dd, J=1.6, 8.0 Hz).

IR (ATR) cm⁻¹: 1621, 1565, 1461, 1384, 1141, 980.

mp: 162-163° C.

MS m/z: 477 (M⁺+H).

FAB-MS: 477.0366 (Calcd for C₂₃H₁₆ClF₂O₅S: 477.0375).

Referential Example 242-[(tert-Butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole

An acetonitrile (3 ml) solution of 2,5-difluorobenzaldehyde (164 μl, 1.5mmol), 1-methylbenzimidazole (132 mg, 1 mmol), di-tert-butyl dicarbonate(252 μl, 1.1 mmol) was stirred at room temperature for 20 hours. Theprecipitate thus formed was collected by filtration, and triturated withhexane, whereby the title compound (310 mg, 83%) was obtained as a whitesolid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.45 (9H, s), 3.86 (3H, s), 6.9-7.0 (2H, m),7.12 (1H, s), 7.22-7.35 (3H, m), 7.45 (1H, m), 7.77 (1H, d, J=8.0 Hz).

IR (ATR) cm⁻¹: 1733, 1492, 1270, 1257, 1137, 852.

mp: 163-164° C.

MS m/z: 375 (M⁺+H).

Referential Example 252-[(tert-Butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-methyl-5-chloro-1H-benzimidazole

An acetonitrile (6 ml) solution of 2,5-difluorobenzaldehyde (327 μl, 3mmol), 5-chloro-1-methylimidazole (187 μl, 2 mmol), and di-tert-butyldicarbonate (50 μl, 2.2 mmol) was stirred at room temperature for 20hours. The precipitate thus formed was collected by filtration andtriturated with hexane, whereby the title compound (472 mg, 66%) wasobtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.48 (9H, s), 3.67 (3H, s), 6.88-7.1 (4H, m),7.39 (1H, m)

IR (ATR) cm⁻¹: 1739, 1496, 1257, 1149, 1080, 858.

mp: 125-126° C.

MS m/z: 359 (M⁺+H).

Referential Example 26 2-[(2,5-Difluorophenyl)-hydroxymethyl]thiazole

To a tetrahydrofuran (10 ml) solution of 2-bromothiazole (180 μg, 2mmol) was added dropwise n-butyl lithium (1.40 ml, 2.2 mmol) at −78° C.After stirring for 10 minutes, 2,5-difluorobenzaldehyde (238 μl, 2.2mmol) was added and while stirring, the temperature of the mixture wasgradually raised to 0° C. The reaction was then quenched by the additionof an aqueous solution of ammonium chloride, followed by the addition ofether. The ether layer was washed with water and brine, and then, driedover anhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography (hexane:ethyl acetate=1:1), whereby the titlecompound (358 mg, 79%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 3.77 (1H, d, J=4.0 Hz), 6.33 (1H, d, J=4.0Hz), 6.95-7.10 (2H, m), 7.24 (1H, m), 7.34 (1H, d, J=3.6 Hz), 7.75 (1H,d, J=3.6 Hz).

IR (ATR) cm⁻¹: 3224, 1489, 1238, 1172, 1128, 818.

MS m/z: 228 (M⁺+H).

Referential Example 272-[(tert-Butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-(4-methoxyphenyl)-1H-benzimidazole

An acetonitrile (6 ml) solution of 2,5-difluorobenzaldehyde (327 μl, 3mmol), 1-(4-methoxyphenyl)imidazole (348 mg, 2 mmol) and di-tert-butyldicarbonate (504 μl, 2.2 mmol) was stirred at room temperature for 20hours. The reaction mixture was concentrated and then, the residue waspurified by silica gel chromatography (hexane:ethyl acetate=5:1-1:1),whereby the title compound (774 mg, 93%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.40 (9H, s), 3.86 (3H, s), 6.76 (1H, s),6.90-7.00 (4H, m), 7.02 (1H, s), 7.11 (1H, s), 7.26 (2H, m), 7.33 (1H,m).

IR (ATR) cm⁻¹: 1741, 1513, 1494, 1243, 1155, 858, 835.

MS m/z: 417 (M⁺+H).

Example 1462-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole

Trifluoroacetic acid (2.0 ml) was added to the2-[(tert-butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole(204 mg, 0.545 mmol) obtained in Referential Example 24 and the mixturewas stirred at room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure. Dioxane was added to the residue,followed by concentration under reduced pressure.

The residue was dissolved in thionyl chloride (1.0 ml). To the resultingsolution was added a drop of dimethylformamide and the mixture wasstirred at room temperature for 16 hours. The reaction mixture wasconcentrated under reduced pressure. Dioxane was added to the residue,followed by concentration under reduced pressure.

The residue was dissolved in dimethylformamide (5.0 ml). To theresulting solution were added 4-chlorobenzenethiol (118 mg, 0.82 mmol)and potassium carbonate (451 mg, 3.27 mmol) and the mixture was stirredat 50° C. for 2 hours. The reaction mixture was allowed to stand untilit became room temperature. Then, ethyl ether (60 ml) was added to thereaction mixture. The mixture was washed with water and brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel chromatography(hexane:ethyl acetate=10:1-5:1), whereby the title compound (195 mg,89%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 3.67 (3H, s), 5.91 (1H, s), 6.87-6.93 (2H,m), 7.19 (2H, d, J=8.8 Hz), 7.27 (2H, d, J=8.8 Hz), 7.25-7.33 (3H, m),7.60 (1H, m), 7.85 (1H, m).

IR (ATR) cm⁻¹: 1492, 1388, 1238, 193, 820.

MS m/z: 401 (M⁺+H).

Example 1472-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-1-methyl-5-chloro-1H-imidazole

Trifluoroacetic acid (10 ml) was added to the2-[(tert-butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-methyl-5-chloro-1H-imidazole(404 mg, 1.13 mmol) obtained in Referential Example 25 and the mixturewas stirred at room temperature for 3 hours. The reaction mixture wasconcentrated under reduced pressure. Dioxane was added to the residue,followed by concentration under reduced pressure.

The residue was dissolved in thionyl chloride (2.0 ml). To the resultingsolution was added a drop of dimethylformamide and the mixture wasstirred at room temperature for 17 hours. The reaction mixture wasconcentrated under reduced pressure. Dioxane was added to the residue,followed by concentration under reduced pressure.

The residue was dissolved in dimethylformamide (5.0 ml). To theresulting solution were added 4-chlorobenzenethiol (244 mg, 1.69 mmol)and potassium carbonate (936 mg, 6.78 mmol). The mixture was stirred at50° C. for 2 hours. After the reaction mixture was allowed to standuntil it became room temperature, ethyl ether (60 ml) was added thereto.The mixture was washed with water and brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (hexane:ethylacetate=10:1-5:1), whereby the title compound (195 mg, 89%) was obtainedas a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 3.57 (3H, s), 5.67 (1H, s), 6.89-6.95 (2H,m), 6.97 (1H, s), 7.20 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 7.54(1H, m).

IR (ATR) cm⁻¹: 1490, 1473, 1162, 1012, 821, 806.

MS m/z: 386 (M⁺+H).

Example 1482-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]thiazole

In thionyl chloride (1.5 ml) was dissolved the2-[(2,5-difluorophenyl)-hydroxymethyl]thiazole (348 mg, 1.53 mmol)obtained in Referential Example 26. To the resulting solution was addeda drop of dimethylformamide and the mixture was stirred at roomtemperature for 14 hours. The reaction mixture was concentrated underreduced pressure. Dioxane was added to the residue, followed byconcentration under reduced pressure.

The residue was dissolved in dimethylformamide (10.0 ml). To theresulting solution were added 4-chlorobenzenethiol (332 mg, 2.3 mmol)and potassium carbonate (845 mg, 6.12 mmol) and the mixture was stirredat 50° C. for 2 hours. After the reaction mixture was allowed to standuntil it became room temperature, ethyl ether (60 ml) was added thereto.The mixture was washed with water and brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (hexane:ethylacetate=10:1-6:1), whereby the title compound (130 mg, 24%) was obtainedas a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 6.04 (1H, s), 6.90-7.06 (2H, m), 7.22 (2H, d,J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz), 7.15-7.35 (2H, m), 7.76 (1H, d, J=3.2Hz).

IR (ATR) cm⁻¹: 1489, 1475, 1093, 1012, 817, 725.

MS m/z: 354 (M⁺+H).

Example 1492-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-1-(4-methoxyphenyl)-1H-imidazole

Trifluoroacetic acid (10 ml) was added to the2-[(tert-butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-(4-methoxyphenyl)-1H-imidazole(667 mg, 1.6 mmol) obtained in Referential Example 27. The mixture wasstirred at room temperature for 3 hours. The reaction mixture wasconcentrated under reduced pressure. Dioxane was added to the residue,followed by concentration under reduced pressure.

The residue was dissolved in thionyl chloride (2.0 ml) and a drop ofdimethylformamide was added to the resulting solution. The mixture wasstirred at room temperature for 17 hours. The reaction mixture was thenconcentrated under reduced pressure. Dioxane was added to the residue,followed by concentration under reduced pressure.

The residue was dissolved in dimethylformamide (5.0 ml), and4-chlorobenzenethiol (347 mg, 2.4 mmol) and potassium carbonate (1.32 g,9.6 mmol) were added to the resulting solution. The mixture was stirredat 50° C. for 2 hours. After the reaction mixture was allowed to standuntil it became room temperature, ethyl ether (60 ml) was added thereto.The mixture was washed with water and brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (hexane:ethylacetate=10:1-5:1) and crystallized from ethanol, whereby the titlecompound (535 mg, 75%) was obtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 3.86 (3H, s), 5.57 (1H, s), 6.8-6.9 (3H, m),6.91 (2H, d, J=8.4 Hz), 7.00 (2H, d, J=8.4 Hz), 7.06 (2H, d, J=6.8 Hz),7.11 (2H, d, J=6.8 Hz), 7.16 (1H, s), 7.81 (1H, m).

IR (ATR) cm⁻¹: 1513, 1475, 1240, 1037, 821.

MS m/z: 443 (M⁺+H).

Example 1502-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole(Compound A) and2-[[(4-chlorophenyl)sulfinyl]-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole(Compound B)

Compound A Compound B

Hexaammonium heptamolybdate tetrahydrate (60 mg) was added to a methanol(12 ml) solution of the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole(190 mg, 0.474 mmol) obtained in Example 146. To the resulting mixturewas added 30% aqueous hydrogen peroxide (6 ml), followed by stirring for17 hours. Ethyl acetate (60 ml) was added to the reaction mixture. Theresulting mixture was washed with water and brine, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (hexane:ethylacetate=6:1-4:1), whereby a nonpolar compound (Compound A) (48 mg, 23%)was obtained as needle crystals and a polar compound (Compound B) (23mg, 12%) was obtained as a white solid.

Compound A

¹H-NMR (400 MHz, CDCl₃) δ: 3.90 (3H, s), 6.14 (1H, s), 6.9-7.1 (2H, m),7.26-7.42 (3H, m), 7.39 (2H, d, J=8.8 Hz), 7.46 (2H, d, J=8.8 Hz), 7.81(1H, d, J=8.0 Hz), 8.16 (1H, m).

IR (ATR) cm⁻¹: 1726, 1606, 1493, 1360, 1184, 1085, 768.

mp: 213-214° C.

MS m/z: 433 (M⁺+H).

Anal. calcd for C₂₁H₁₅ClF₂N₂OS: C, 58.27%; H, 3.49%; N, 6.47%; S, 7.41%;Cl, 8.19%; F, 8.78%. Found: C, 58.08%; H, 3.62%; N, 6.53%; S, 7.35%; Cl,8.10%; F, 8.74%.

Compound B

¹H-NMR (400 MHz, CDCl₃) δ: 3.35 (½*3H, s), 3.78 (½*3H, s), 5.52 (½*1H,s), 5.57 (½*1H, s), 6.78-7.1 (2H, m), 7.2-7.4 (7H, m), 7.76-7.95 (2H,m).

IR (ATR) cm⁻¹: 1490, 1238, 1054, 820, 731.

mp: 130-131° C.

MS m/z: 417 (M⁺+H).

FAB-MS: 477.0646 (Calcd for C₂₁H₁₆ClF₂N₂OS: 477.0640).

Example 1512-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-1-methyl-5-chloro-1H-imidazole

To a methanol (12 ml) solution of the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-1-methyl-5-chloro-1H-imidazole(141 mg, 0.37 mmol) obtained in Example 147 was added hexaammoniumheptamolybdate tetrahydrate (60 mg). To the resulting mixture was added30% aqueous hydrogen peroxide (6 ml), followed by stirring for 64 hours.Ethyl acetate (60 ml) was added and the mixture was washed with waterand brine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was then crystallized from ethanol,whereby the title compound (103 mg, 67%) was obtained as colorlessneedle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 3.71 (3H, s), 5.88 (1H, s), 6.93-7.08 (2H,m), 7.03 (1H, s), 7.43 (4H, s), 7.98 (1H, m).

IR (ATR) cm⁻¹: 1490, 1467, 1313, 1149, 1079, 818, 729.

mp: 179-180° C.

MS m/z: 417 (M⁺+H).

Anal. calcd for C₁₇H₁₂Cl₂F₂N₂O₂S: C, 48.90%; H, 2.93%; N, 6.71%; S,7.68%; Cl, 16.99%; F, 9.11%. Found: C, 48.90%; H, 2.93%; N, 6.77%; S,7.80%; Cl, 17.02%; F, 9.19%.

Example 1522-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]thiazole

To a methanol (6.0 ml) solution of the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]thiazole (124 mg,0.35 mmol) obtained in Example 148 was added hexaammonium heptamolybdatetetrahydrate (30 mg). To the resulting mixture was added 30% aqueoushydrogen peroxide (3 ml), followed by stirring for 15 hours. Ethylacetate (60 ml) was then added and the mixture was washed with water andbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was crystallized from ethanol, whereby thetitle compound (91 mg, 67%) was obtained as colorless columnar crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 6.21 (1H, s), 6.92-7.08 (2H, m), 7.41 (2H, d,J=8.8 Hz), 7.45 (1H, d, J=3.6 Hz), 7.56 (2H, d, J=8.8 Hz), 7.86 (1H, d,J=3.6 Hz), 7.94 (1H, m).

IR (ATR) cm⁻¹: 1488, 1319, 1149, 1076, 817, 727.

mp: 163-164° C.

MS m/z: 386 (M⁺+H).

Anal. calcd for C₁₆H₁₀ClF₂NO₂S₂: C, 49.81%; H, 2.61%; N, 3.63%; S,16.62%; Cl, 9.19%; F, 9.85%. Found: C, 49.98%; H, 2.61%; N, 3.77%; S,16.60%; Cl, 9.25%; F, 9.87%.

Example 1532-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]1-(4-methoxyphenyl)-1H-imidazole

To a methanol (12 ml) solution of the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-1-(4-methoxyphenyl)-1H-benzimidazole(118 mg, 0.27 mmol) obtained in Example 149 was added hexaammoniumheptamolybdate tetrahydrate (60 mg). To the resulting mixture was added30% aqueous hydrogen peroxide (6 ml), followed by stirring for 64 hours.Ethyl acetate (60 ml) was added, and the mixture was washed with waterand brine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was crystallized from ethanol, whereby thetitle compound (76 mg, 60%) was obtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 3.89 (3H, s), 5.83 (1H, s), 6.93-7.05 (4H,m), 6.97 (2H, d, J=8.8 Hz), 7.01 (2H, d, J=8.8 Hz), 7.38 (2H, d, J=8.8Hz), 7.41 (2H, d, J=8.8 Hz), 8.15 (1H, m).

IR (ATR) cm⁻¹: 1513, 1492, 1332, 1155, 836.

mp: 150-151° C.

MS m/z: 475 (M⁺+H).

Anal. calcd for C₂₃H₁₇ClF₂N₂O₃S: C, 58.13%; H, 3.61%; N, 5.90%; S,6.75%; Cl, 7.47%; F, 8.00%. Found: C, 58.09%; H, 3.51%; N, 5.99%; S,6.88%; Cl, 7.48%; F, 8.06%.

Referential Example 28 5-(Methylsulfonyl)-1-pentanol

To a dichloromethane (25 ml) solution of 5-(methylthio)-1-pentanol (682mg, 5.08 mmol) was added 3-chloroperbenzoic acid (2.10 g, 12.2 mmol) andthe resulting mixture was stirred at room temperature for 2 hours. Afterconcentration under reduced pressure, diethyl ether was added to theresidue and the mixture was extracted with water. After the organiclayer was extracted twice with water, the water layers were combined andconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography, and the fraction obtainedfrom the dichloromethane:methanol=19:1 eluate was concentrated underreduced pressure, whereby the title compound (517 mg, 3.11 mmol, 61%)was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.50-1.67 (4H, m), 1.84-1.94 (2H, m), 2.90(3H, s), 3.03 (2H, t, J=8.0 Hz), 3.68 (2H, t, J=6.1 Hz).

Referential Example 29 5-(Methylsulfonyl)pentanal

To a dichloromethane (15 ml) solution of 5-(methylsulfonyl)-1-pentanol(344 mg, 2.07 mmol), dimethylsulfoxide (0.441 ml, 6.21 mmol) andtriethylamine (1.15 ml, 8.28 ml) was added a sulfur trioxide pyridinecomplex (659 mg, 4.14 mmol) at 0° C. and the mixture was stirred at roomtemperature for 3 hours. After the reaction mixture was washed withwater, the organic layer was dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was subjected to flash silica gel chromatography, and thefraction obtained from the ethyl acetate eluate was concentrated underreduced pressure, whereby the title compound (183 mg, 1.11 mmol, 54%)was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.76-1.97 (4H, m), 2.55 (2H, t, J=7.1 Hz),2.91 (3H, s), 3.04 (2H, t, J=7.8 Hz), 9.79 (1H, s).

Referential Example 301-(2,5-Difluorophenyl)-5-(methylsulfonyl)-1-pentanol

A tetrahydrofuran (5 ml) solution of 1-bromo-2,5-difluorobenzene (0.151ml, 1.34 mmol) was stirred at −78° C. To the resulting mixture was addeda hexane solution (0.843 ml, 1.34 mmol) of n-butyl lithium. The reactionmixture was added to a tetrahydrofuran (5 ml) solution of5-(methylsulfonyl)pentanal (183 mg, 1.11 mmol) at −78° C. and at thesame temperature, stirring was conducted for 30 minutes. After elevatingthe temperature of the reaction mixture to room temperature, diethylether was added thereto. The resulting mixture was washed successivelywith a saturated aqueous solution of ammonium chloride and a saturatedaqueous solution of sodium bicarbonate. The organic layer was then driedover anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected to flashsilica gel chromatography, and the fraction obtained from thehexane:ethyl acetate=1:2 eluate was concentrated under reduced pressure,whereby the title compound (116 mg, 0.42 mmol, 37%) was obtained as acolorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.49-1.69 (2H, m), 1.71-1.97 (4H, m), 2.89(3H, s), 3.01 (2H, t, J=8.1 Hz), 5.02 (1H, t, J=6.2 Hz), 6.88-7.01 (2H,m), 7.16-7.22 (1H, m).

MS m/z: 296 (M⁺+NH₄).

Referential Example 311-(2,5-Difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate

To a dichloromethane (5 ml) solution of1-(2,5-difluorophenyl)-5-(methylsulfonyl)-1-pentanol (278 mg, 1.00 mmol)were successively added triethylamine (0.209 ml, 1.50 mmol) andmethanesulfonyl chloride (0.115 ml, 1.50 mmol) at 0° C. The resultingmixture was stirred at room temperature for 3 hours. The reactionmixture was washed with a saturated aqueous solution of sodiumbicarbonate. Then, the organic layer was dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure. The residue was subjected to flash silica gel chromatography,and the fraction obtained from the hexane:ethyl acetate=1:1 eluate wasconcentrated under reduced pressure, whereby the title compound (278 mg,0.78 mmol, 78%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.48-1.71 (2H, m), 1.85-1.98 (3H, m),2.03-2.13 (1H, m), 2.90 (3H, s), 2.90 (3H, s), 3.02 (2H, t, J=7.8 Hz),5.82 (1H, dd, J=8.6, 5.1 Hz), 7.01-7.19 (3H, m).

MS m/z: 374 (M⁺+NH₄).

Example 1541,4-Difluoro-2-[1-[(4-methoxyphenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene

To an N,N-dimethylformamide (2 ml) solution of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (139mg, 0.39 mmol) were successively added 4-methoxybenzenethiol (0.058 ml,0.47 mmol) and potassium carbonate (81 mg, 0.59 mmol). The resultingmixture shaken at room temperature for 15 hours. Ethyl acetate was addedto the residue. The mixture was washed with a saturated aqueous solutionof ammonium chloride. Then, the organic layer was dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated underreduced pressure.

The residue thus obtained was dissolved in methanol (2 ml), followed bythe addition of a water (2 ml) solution of Oxone (potassiumperoxymonosulfate compound, 2KHSO₅.KHSO₄.K₂SO₄) (480 mg, 0.78 mmol) at0° C. After shaking at room temperature for 3 hours, dichloromethane wasadded and the mixture was washed with water. The organic layer was driedover anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified bypreparative high performance liquid chromatography (using a mixedsolvent of water/acetonitrile/formic acid). The resulting solid waswashed with diethyl ether and then, collected by filtration, whereby thetitle compound (86 mg, 0.20 mmol, 51%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.34-1.52 (2H, m), 1.79-1.95 (2H, m),2.05-2.16 (1H, m), 2.42-2.52 (1H, m), 2.87 (3H, s), 2.92-2.99 (2H, m),3.85 (3H, s), 4.48 (1H, dd, J=11.0, 2.9 Hz), 6.80-6.89 (1H, m), 6.87(2H, d, J=8.8 Hz), 6.94-7.00 (1H, m), 7.19-7.25 (1H, m), 7.51 (2H, d,J=8.8 Hz).

IR (ATR) cm⁻¹: 2951, 1595, 1496, 1271, 1132, 1084, 1022, 970.

Anal. Calcd for C₁₉H₂₂F₂O₅S₂: C, 52.76; H, 5.13; F, 8.79.

Found: C, 52.57; H, 5.13; F, 8.71.

MS m/z: 433 (M⁺+H).

Example 1551,4-Difluoro-2-[5-(methylsulfonyl)-1-(phenylsulfonyl)pentyl]benzene

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and thiophenol (0.037 ml, 0.36 mmol), the title compound(83 mg, 0.21 mmol, 58%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.34-1.52 (2H, m), 1.79-1.97 (2H, m),2.07-2.20 (1H, m), 2.44-2.55 (1H, m), 2.87 (3H, s), 2.90-3.01 (2H, m),4.51 (1H, dd, J=10.9, 3.6 Hz), 6.75-6.84 (1H, m), 6.92-7.00 (1H, m),7.19-7.27 (1H, m), 7.38-7.46 (2H, m), 7.55-7.65 (3H, m).

MS m/z: 420 (M⁺+NH₄).

Example 1561,4-Difluoro-2-[1-[(4-methylphenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (139mg, 0.39 mmol) and p-toluenethiol (58 mg, 0.47 mmol), the title compound(65 mg, 0.16 mmol, 40%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.33-1.51 (2H, m), 1.77-1.96 (2H, m),2.03-2.16 (1H, m), 2.37-2.51 (1H, m), 2.40 (3H, s), 2.87 (3H, s),2.90-3.00 (2H, m), 4.49 (1H, dd, J=11.1, 3.8 Hz), 6.79-6.88 (1H, m),6.94-7.02 (1H, m), 7.19-7.26 (1H, m), 7.21 (2H, d, J=7.8 Hz), 7.48 (2H,d, J=7.8 Hz).

IR (ATR) cm⁻¹: 2943, 1597, 1498, 1269, 1142, 1084, 957, 868.

Anal. Calcd for C₁₉H₂₂F₂O₄S₂: C, 54.79; H, 5.32; F, 9.12.

Found: C, 54.67; H, 5.30; F, 9.10.

MS m/z: 417 (M⁺+H).

Example 1572-[1-[(3-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]-1,4-difluorobenzene

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and 3-chlorobenzenethiol (0.041 ml, 0.36 mmol), the titlecompound (6.3 mg, 0.014 mmol, 4%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.34-1.54 (2H, m), 1.79-1.97 (2H, m),2.08-2.21 (1H, m), 2.41-2.56 (1H, m), 2.88 (3H, s), 2.90-3.03 (2H, m),4.51 (1H, dd, J=10.6, 3.4 Hz), 6.78-6.90 (1H, m), 6.95-7.06 (1H, m),7.19-7.29 (1H, m), 7.36 (1H, t, J=7.8 Hz), 7.49 (1H, d, J=7.8 Hz), 7.55(1H, d, J=7.8 Hz), 7.56 (1H, s).

MS m/z: 437 (M⁺+H).

Example 1581,4-Difluoro-2-[1-[(3-methylphenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and m-toluenethiol (0.043 ml, 0.36 mmol), the titlecompound (26 mg, 0.062 mmol, 17%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.33-1.52 (2H, m), 1.78-1.96 (2H, m),2.03-2.19 (1H, m), 2.34 (3H, s), 2.39-2.51 (1H, m), 2.87 (3H, s),2.91-2.99 (2H, m), 4.50 (1H, dd, J=11.0, 3.4 Hz), 6.78-6.86 (1H, m),6.93-7.02 (1H, m), 7.19-7.33 (2H, m), 7.36-7.44 (3H, m).

MS m/z: 417 (M⁺+H).

Example 1591,4-Difluoro-2-[1-[(3-methoxyphenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and 3-methoxybenzenethiol (0.044 ml, 0.36 mmol), thetitle compound (25 mg, 0.059 mmol, 16%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.34-1.51 (2H, m), 1.79-1.95 (2H, m),2.06-2.18 (1H, m), 2.42-2.52 (1H, m), 2.87 (3H, s), 2.90-3.00 (2H, m),3.75 (3H, s), 4.52 (1H, dd, J=11.5, 4.6 Hz), 6.80-6.87 (1H, m),6.94-7.01 (1H, m), 7.05 (1H, s), 7.10 (1H, d, J=8.1 Hz), 7.21 (1H, d,J=8.1 Hz), 7.21-7.29 (1H, m), 7.32 (1H, t, J=8.1 Hz).

MS m/z: 433 (M⁺+H).

Example 1601,4-Difluoro-2-[1-[(4-fluorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and 4-fluorobenzenethiol (0.038 ml, 0.36 mmol), the titlecompound (35 mg, 0.083 mmol, 23%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.38-1.53 (2H, m), 1.82-1.97 (2H, m),2.08-2.20 (1H, m), 2.47-2.57 (1H, m), 2.88 (3H, s), 2.92-3.02 (2H, m),4.50 (1H, dd, J=11.0, 4.4 Hz), 6.78-6.88 (1H, m), 6.95-7.02 (1H, m),7.05-7.13 (2H, m), 7.22-7.32 (1H, m), 7.57-7.64 (2H, m).

MS m/z: 438 (M⁺+NH₄).

Example 1614-[[1-(2,5-Difluorophenyl)-5-(methylsulfonyl)pentyl]sulfonyl]phenol

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and 4-mercaptophenol (45 mg, 0.36 mmol), the titlecompound (63 mg, 0.15 mmol, 42%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.34-1.52 (2H, m), 1.80-1.93 (2H, m),2.03-2.18 (1H, m), 2.42-2.52 (1H, m), 2.88 (3H, s), 2.90-3.00 (2H, m),4.47 (1H, dd, J=10.8, 3.2 Hz), 5.44 (1H, s), 6.78-6.87 (1H, m), 6.81(2H, d, J=8.8 Hz), 6.94-7.01 (1H, m), 7.19-7.28 (1H, m), 7.48 (2H, d,J=8.8 Hz).

MS m/z: 419 (M⁺+H).

Example 1621-[[1-(2,5-Difluorophenyl)-5-(methylsulfonyl)pentyl]sulfonyl]naphthalene

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and 1-naphthalenethiol (57 mg, 0.36 mmol), the titlecompound (48 mg, 0.11 mmol, 29%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.29-1.46 (2H, m), 1.72-1.90 (2H, m),2.13-2.26 (1H, m), 2.29-2.40 (1H, m), 2.83 (3H, s), 2.82-2.93 (2H, m),4.79 (1H, dd, J=11.3, 3.9 Hz), 6.66-6.75 (1H, m), 6.87-6.94 (1H, m),7.24-7.31 (1H, m), 7.45 (1H, t, J=7.6 Hz), 7.58-7.62 (2H, m), 7.94 (1H,d, J=8.1 Hz), 8.01 (1H, d, J=7.6 Hz), 8.08 (1H, d, J=8.1 Hz), 8.73 (1H,d, J=8.6 Hz).

MS m/z: 453 (M⁺+H).

Example 1632-[[1-(2,5-Difluorophenyl)-5-(methylsulfonyl)pentyl]sulfonyl]-1H-benzimidazole

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and 2-mercaptobenzimidazole (54 mg, 0.36 mmol), the titlecompound (62 mg, 0.14 mmol, 39%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.28-1.53 (2H, m), 1.78-1.96 (2H, m),2.17-2.30 (1H, m), 2.42-2.53 (1H, m), 2.86 (3H, s), 2.88-3.02 (2H, m),5.03 (1H, dd, J=11.3, 3.9 Hz), 6.90-7.04 (2H, m), 7.13-7.20 (1H, m),7.39-7.47 (2H, m), 7.50 (1H, br s), 7.90 (1H, br s), 10.08 (1H, br s).

MS m/z: 443 (M⁺+H).

Example 1644-[[1-(2,5-Difluorophenyl)-5-(methylsulfonyl)pentyl]sulfonyl]pyridine

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and 4-mercaptopyridine (40 mg, 0.36 mmol), the titlecompound (38 mg, 0.093 mmol, 26%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.27-1.60 (2H, m), 1.70-1.90 (2H, m),2.00-2.13 (1H, m), 2.35-2.48 (1H, m), 2.88 (3H, s), 2.90-3.04 (2H, m),4.56 (1H, dd, J=10.6, 4.3 Hz), 6.78-6.85 (1H, m), 6.95-7.03 (1H, m),7.22-7.30 (1H, m), 7.45 (2H, d, J=5.2 Hz), 8.75 (2H, d, J=5.2 Hz).

MS m/z: 404 (M⁺+H).

Example 1652-[[1-(2,5-Difluorophenyl)-5-(methylsulfonyl)pentyl]sulfonyl]pyridine

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and 2-mercaptopyridine (40 mg, 0.36 mmol), the titlecompound (72 mg, 0.18 mmol, 50%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.36-1.52 (2H, m), 1.78-1.96 (2H, m),2.10-2.21 (1H, m), 2.35-2.46 (1H, m), 2.87 (3H, s), 2.90-3.03 (2H, m),5.11 (1H, dd, J=10.9, 3.8 Hz), 6.82-6.91 (1H, m), 6.92-6.98 (1H, m),7.24-7.31 (1H, m), 7.48-7.54 (1H, m), 7.79-7.87 (2H, m), 8.75 (1H, d,J=4.6 Hz).

MS m/z: 404 (M⁺+H).

Example 1662-[[1-(2,5-Difluorophenyl)-5-(methylsulfonyl)pentyl]sulfonyl]quinoline

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and 2-quinolinethiol (58 mg, 0.36 mmol), the titlecompound (90 mg, 0.20 mmol, 55%) was obtained as a colorless foam.

¹H-NMR (400 MHz, CDCl₃) δ: 1.39-1.59 (2H, m), 1.80-1.99 (2H, m),2.13-2.26 (1H, m), 2.42-2.53 (1H, m), 2.86 (3H, s), 2.91-3.02 (2H, m),5.33 (1H, dd, J=11.1, 3.1 Hz), 6.74-6.82 (1H, m), 6.88-6.96 (1H, m),7.31-7.36 (1H, m), 7.72 (1H, t, J=7.1 Hz), 7.86-7.92 (3H, m), 8.24 (1H,d, J=8.5 Hz), 8.29 (1H, d, J=8.8 Hz).

MS m/z: 454 (M⁺+H).

Example 1672-[[1-(2,5-Difluorophenyl)-5-(methylsulfonyl)pentyl]sulfonyl]pyrimidine

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl-methanesulfonate (127mg, 0.36 mmol) and 2-mercaptopyrimidine (40 mg, 0.36 mmol), the titlecompound (55 mg, 0.14 mmol, 38%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.38-1.60 (2H, m), 1.79-1.98 (2H, m),2.11-2.25 (1H, m), 2.37-2.47 (1H, m), 2.88 (3H, s), 2.90-3.02 (2H, m),5.31 (1H, dd, J=10.5, 3.4 Hz), 6.89-7.02 (2H, m), 7.33-7.39 (1H, m),7.52 (1H, t, J=4.9 Hz), 8.91 (2H, d, J=4.9 Hz).

MS m/z: 405 (M⁺+H).

Example 1685-[[1-(2,5-Difluorophenyl)-5-(methylsulfonyl)pentyl]sulfonyl]-1-methyl-1H-tetrazole

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and 1-methyl-5-mercapto-1,2,3,4-tetrazole (42 mg, 0.36mmol), the title compound (75 mg, 0.18 mmol, 52%) was obtained as acolorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.43-1.65 (2H, m), 1.82-2.01 (2H, m),2.18-2.31 (1H, m), 2.49-2.60 (1H, m), 2.90 (3H, s), 2.92-3.06 (2H, m),4.10 (3H, s), 5.12 (1H, dd, J=11.0, 3.7 Hz), 7.03-7.22 (3H, m).

MS m/z: 409 (M⁺+H).

Example 1692-[[1-(2,5-Difluorophenyl)-5-(methylsulfonyl)pentyl]sulfinyl]-1-methyl-1H-imidazole(Compound A) and2-[[1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl]sulfonyl]-1-methyl-1H-imidazole(Compound B)

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and 2-mercapto-1-methylimidazole (41 mg, 0.36 mmol), thetitle compound A (45 mg, 0.12 mmol, 32%) and the title compound B (47mg, 0.11 mmol, 32%) were obtained as a yellow oil and as a colorlessoil, respectively.

Compound A

¹H-NMR (400 MHz, CDCl₃) δ: 1.45-1.67 (2H, m), 1.82-2.02 (2H, m),2.09-2.21 (1H, m), 2.41-2.52 (1H, m), 2.89 (3H, s), 2.92-3.08 (2H, m),3.66 (3H, s), 4.91 (1H, dd, J=11.1, 4.5 Hz), 6.78-6.84 (1H, m), 6.90(1H, s), 6.93-7.01 (2H, m), 7.12 (1H, s).

MS m/z: 391 (M⁺+H).

Compound B

¹H-NMR (400 MHz, CDCl₃) δ: 1.37-1.66 (2H, m), 1.81-1.96 (2H, m),2.12-2.23 (1H, m), 2.45-2.56 (1H, m), 2.88 (3H, s), 2.91-3.03 (2H, m),3.59 (3H, s), 4.89 (1H, dd, J=10.9, 4.0 Hz), 6.93 (1H, d, J=0.7 Hz),6.97-7.08 (3H, m), 7.19 (1H, d, J=0.7 Hz).

MS m/z: 407 (M⁺+H).

Example 1702-[[1-(2,5-Difluorophenyl)-5-(methylsulfonyl)pentyl]sulfinyl]-1,3-benzothiazole

In a similar manner to Example 154 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and 2-mercaptobenzothiazole (60 mg, 0.36 mmol), the titlecompound (78 mg, 0.18 mmol, 49%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.37-1.48 (2H, m), 1.72-1.91 (2H, m),2.09-2.29 (2H, m), 2.83 (3H, s), 2.85-2.95 (2H, m), 4.66 (1H, dd,J=10.5, 4.1 Hz), 7.01-7.08 (3H, m), 7.48-7.50 (2H, m), 7.87-8.08 (2H,m).

MS m/z: 444 (M⁺+H).

Example 1712-[1-[(2-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]-1,4-difluorobenzene

To an N,N-dimethylformamide (2 ml) solution of the1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) obtained in Referential Example 31 were successivelyadded 2-chlorobenzenethiol (0.041 ml, 0.36 mmol) and potassium carbonate(62 mg, 0.45 mmol). At room temperature, the resulting mixture wasshaken for 4 hours. Ethyl acetate was added to the reaction mixture. Themixture was washed with water and then, the organic layer was dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure.

The residue thus obtained was dissolved in methanol (2 ml), followed bythe addition of a water (2 ml) solution of Oxone (potassiumperoxymonosulfate compound, 2KHSO₅.KHSO₄.K₂SO₄) (439 mg, 0.71 mmol) at0° C. After shaking at room temperature for 14 hours, the reactionmixture was added with dichloromethane and the mixture was washed withwater. The organic layer was dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure.

The residue thus obtained was dissolved in dichloromethane (4 ml) and at0° C., 3-chloroperbenzoic acid (95 mg, 0.36 mmol) was added to theresulting solution. The reaction mixture was shaken at room temperaturefor 4 hours, and then washed with a 1N sodium hydroxide solution. Theorganic layer was dried over anhydrous sodium sulfate. After filtration,the filtrate was concentrated under reduced pressure. The residue waspurified by preparative high performance liquid chromatography (using amixed solvent of water/acetonitrile/formic acid). The resulting solidwas washed with diethyl ether and then, collected by filtration, wherebythe title compound (59 mg, 0.14 mmol, 38%) was obtained as a whitepowder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.39-1.60 (2H, m), 1.82-1.97 (2H, m),2.10-2.22 (1H, m), 2.37-2.48 (1H, m), 2.87 (3H, s), 2.91-3.02 (2H, m),5.13 (1H, dd, J=10.7, 3.7 Hz), 6.79-6.87 (1H, m), 6.90-6.97 (1H, m),7.23-7.33 (2H, m), 7.46-7.55 (2H, m), 8.75 (1H, dd, J=7.9, 1.6 Hz).

MS m/z: 437 (M⁺+H).

Example 1721,4-Difluoro-2-[1-[(2-fluorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene

In a similar manner to Example 171 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and 2-fluorobenzenethiol (0.040 ml, 0.36 mmol), the titlecompound (71 mg, 0.17 mmol, 47%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.39-1.60 (2H, m), 1.80-1.98 (2H, m),2.10-2.22 (1H, m), 2.44-2.54 (1H, m), 2.88 (3H, s), 2.96 (2H, t, J=7.4Hz), 4.84 (1H, dd, J=10.7, 4.4 Hz), 6.78-6.85 (1H, m), 6.90-6.96 (1H,m), 7.10-7.21 (2H, m), 7.22-7.29 (1H, m), 7.52-7.60 (2H, m).

MS m/z: 421 (M⁺+H).

Example 1731,4-Difluoro-2-[1-[(2-methylphenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene

In a similar manner to Example 171 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and o-toluenethiol (0.042 ml, 0.36 mmol), the titlecompound (38 mg, 0.091 mmol, 25%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.33-1.55 (2H, m), 1.79-1.95 (2H, m),2.09-2.21 (1H, m), 2.37-2.47 (1H, m), 2.63 (3H, s), 2.87 (3H, s),2.92-2.98 (2H, m), 4.61 (1H, dd, J=11.2, 3.4 Hz), 6.75-6.82 (1H, m),6.89-6.97 (1H, m), 7.16 (1H, t, J=7.6 Hz), 7.22-7.31 (2H, m), 7.43 (1H,t, J=7.6 Hz), 7.43 (1H, t, J=8.0 Hz).

MS m/z: 417 (M⁺+H).

Example 1741,4-Difluoro-2-[1-[(2-methoxyphenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene

In a similar manner to Example 171 except for the use of1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl=methanesulfonate (127mg, 0.36 mmol) and 2-methoxybenzenethiol (0.044 ml, 0.36 mmol), thetitle compound (52 mg, 0.12 mmol, 33%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.33-1.55 (2H, m), 1.78-1.96 (2H, m),2.06-2.17 (1H, m), 2.36-2.47 (1H, m), 2.87 (3H, s), 2.90-3.00 (2H, m),4.00 (3H, s), 5.13 (1H, dd, J=11.2, 3.2 Hz), 6.78-6.95 (3H, m), 6.98(1H, d, J=7.8 Hz), 7.27-7.33 (1H, m), 7.46-7.53 (1H, m), 7.63 (1H, dd,J=8.0, 1.7 Hz).

MS m/z: 433 (M⁺+H).

Example 1752-[1-[(4-Chlorophenyl)sulfonyl]-6-(methylsulfonyl)hexyl]-1,4-difluorobenzene

To a toluene (2 ml) solution of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.33mmol) obtained in Example 5 and the 5-(methylsulfonyl)-1-pentanol (110mg, 0.66 mmol) obtained in Referential Example 28 was added a toluene (1ml) solution of cyanomethylenetri-n-butylphosphorane (177 mg, 0.66mmol). The resulting mixture was heated under reflux for 16 hours. Aftercooling the reaction mixture to room temperature, it was concentratedunder reduced pressure. The residue thus obtained was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate=3:2 eluate was concentrated under reducedpressure. The resulting solid was washed with diethyl ether and then,collected by filtration, whereby the title compound (140 mg, 0.31 mmol,94%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.22-1.38 (2H, m), 1.39-1.56 (2H, m),1.73-1.86 (2H, m), 2.03-2.16 (1H, m), 2.41-2.52 (1H, m), 2.88 (3H, s),2.95 (2H, t, J=7.9 Hz), 4.50 (1H, dd, J=11.5, 3.2 Hz), 6.80-6.89 (1H,m), 6.95-7.04 (1H, m), 7.22-7.28 (1H, m), 7.38 (2H, d, J=8.5 Hz), 7.52(2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 2949, 1500, 1475, 1317, 1294, 1275, 1136, 1084, 964, 752.

Anal. Calcd for C₁₉H₂₁ClF₂O₄S₂: C, 50.61; H, 4.69; Cl, 7.86; F, 8.43; S,14.22. Found: C, 50.59; H, 4.67; Cl, 8.04; F, 8.39; S, 14.15.

Referential Example 32 5-Chloro-2-pyridinethiol

After addition of thiourea (152 mg, 2.00 mmol) to an ethanol (4 ml)solution of 2,5-dichloropyridine (296 mg, 2.00 mmol), the resultingmixture was heated under reflux for 18 hours. The reaction mixture wascooled to room temperature, followed by the addition of a water (1 ml)solution of potassium hydroxide (198 mg, 3.00 mmol). The resultingmixture was heated under reflux for 3 hours. After cooling to roomtemperature, to the reaction mixture was added water and then themixture was washed with dichloromethane. The water layer was made acidicwith acetic acid, followed by extraction with dichloromethane. Theorganic layer was dried over anhydrous sodium sulfate. After filtration,the filtrate was concentrated under reduced pressure. The resultingsolid was washed with diethyl ether and then collected by filtration,whereby the title compound (83 mg, 0.57 mmol, 29%) was obtained asyellow powder.

¹H-NMR (400 MHz, CDCl₃) δ: 7.35 (1H, dd, J=9.3, 2.4 Hz), 7.46 (1H, d,J=9.3 Hz), 7.64 (1H, d, J=2.4 Hz).

MS m/z: 146 (M⁺+H).

Example 1765-Chloro-2-[[1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl]thio]pyridine

To a dichloromethane (5 ml) solution of the1-(2,5-difluorophenyl)-5-(methylsulfonyl)-1-pentanol (100 mg, 0.36 mmol)obtained in Referential Example 30 were successively added triethylamine(0.060 ml, 0.43 mmol) and methanesulfonyl chloride (0.033 ml, 0.43 mmol)at 0° C. The resulting mixture was stirred at room temperature for 3hours. The reaction mixture was washed with water, and the organic layerwas dried over anhydrous sodium sulfate. After filtration, the filtratewas concentrated under reduced pressure.

To an N,N-dimethylformamide (4 ml) solution of the resulting residuewere successively added 5-chloro-2-pyridinethiol (52 mg, 0.36 mmol) andpotassium carbonate (62 mg, 0.45 mmol). The resulting mixture wasstirred at room temperature for 3 hours. Ethyl acetate was added to thereaction mixture. After washing with water, the organic layer was driedover anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate=1:1 eluate was concentrated under reducedpressure, whereby the title compound (116 mg, 0.29 mmol, 79%) wasobtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.39-1.64 (2H, m), 1.83-2.17 (4H, m), 2.88(3H, s), 2.92-3.06 (2H, m), 5.20 (1H, t, J=7.6 Hz), 6.84-6.92 (1H, m),6.96-7.02 (1H, m), 7.05 (1H, dd, J=8.6, 0.7 Hz), 7.11-7.18 (1H, m), 7.43(1H, dd, J=8.6, 2.5 Hz), 8.37 (1H, dd, J=2.5, 0.7 Hz).

MS m/z: 406 (M⁺+H).

Example 1775-Chloro-2-[[1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl]sulfonyl]pyridine

To a methanol (2 ml) solution of5-chloro-2-[[1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl]thio]pyridine(100 mg, 0.25 mmol) was added a water (2 ml) solution of Oxone(potassium peroxymonosulfate compound, 2KHSO₅.KHSO₄.K₂SO₄) (303 mg, 0.49mmol) at 0° C. After shaking at room temperature for 22 hours, thereaction mixture was added with dichloromethane and the mixture waswashed with water. The organic layer was dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure. The residue was subjected to flash chromatography on a silicagel column, and the fraction obtained from the hexane:ethyl acetate=1:1eluate was concentrated under reduced pressure, whereby the titlecompound (61 mg, 0.14 mmol, 56%) was obtained as a colorless foam.

¹H-NMR (400 MHz, CDCl₃) δ: 1.37-1.53 (2H, m), 1.80-1.97 (2H, m),2.09-2.20 (1H, m), 2.36-2.48 (1H, m), 2.88 (3H, s), 2.96 (2H, t, J=7.5Hz), 5.07 (1H, dd, J=11.1, 3.8 Hz), 6.86-7.02 (2H, m), 7.23-7.31 (1H,m), 7.74 (1H, d, J=8.3 Hz), 7.79 (1H, dd, J=8.3, 2.2 Hz), 8.67 (1H, d,J=2.2 Hz).

Anal. Calcd for C₁₇H₁₈ClF₂NO₄S₂.0.25H₂O: C, 46.15; H, 4.21; F, 8.59; N,3.17; S, 14.50. Found: C, 46.38; H, 4.11; F, 8.40; N, 3.20; S, 14.22.

MS m/z: 438 (M⁺+H).

Referential Example 33 S-(6-Chloro-3-pyridyl) O-ethyl dithiocarbonate

In 1N hydrochloric acid (10 ml) was dissolved 5-amino-2-chloropyridine(643 mg, 3.00 mmol). A water (1 ml) solution of sodium nitrite (207 mg,3.00 mmol) was added dropwise to the resulting solution at −5° C. Afterthe reaction mixture was stirred at 60° C. for 30 minutes, a water (1ml) solution of potassium O-ethyl dithiocarbonate (481 mg, 3.00 mmol)was added dropwise thereto at the same temperature. The reaction mixturewas then stirred at 80° C. for 1 hour, followed by cooling to roomtemperature. Ethyl acetate was added, and the resulting mixture waswashed with a saturated aqueous solution of sodium bicarbonate. Theorganic layer was dried over anhydrous sodium sulfate. After filtration,the filtrate was concentrated under reduced pressure. The residue wassubjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate=49:1 eluate wasconcentrated under reduced pressure, whereby the title compound (148 mg,0.63 mmol, 21%) was obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.37 (3H, t, J=7.1 Hz), 4.63 (2H, t, J=7.1Hz), 7.41 (1H, d, J=8.3 Hz), 7.76 (1H, dd, J=8.3, 2.4 Hz), 8.45 (1H, d,J=2.4 Hz).

MS m/z: 234 (M⁺+H).

Example 1782-Chloro-5-[[1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl]sulfonyl]pyridine

To an ethanol (3 ml) solution of S-(6-chloro-3-pyridyl) O-ethyldithiocarbonate (145 mg, 0.62 mmol) was added a 1N aqueous solution (3ml) of sodium hydroxide, followed by stirring at 80° C. for 2 hours.After cooling to room temperature, the reaction mixture was added withwater and the mixture was then washed with dichloromethane. The waterlayer was made acidic with acetic acid and then, was extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure, whereby 6-chloro-3-pyridinethiol was obtained as a yellowsolid.

To a dichloromethane (5 ml) solution of the1-(2,5-difluorophenyl)-5-(methylsulfonyl)-1-pentanol (173 mg, 0.62 mmol)obtained in Referential Example 30 were successively added triethylamine(0.130 ml, 0.93 mmol) and methanesulfonyl chloride (0.060 ml, 0.78 mmol)at 0° C. The resulting mixture was stirred at room temperature for 2hours. The reaction mixture was washed with a saturated aqueous solutionof sodium bicarbonate. The organic layer was dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure.

To an N,N-dimethylformamide (6 ml) solution of the residue weresuccessively added 6-chloro-3-pyridinethiol and potassium carbonate (107mg, 0.78 mmol). The resulting mixture was stirred at room temperaturefor 2 hours. After addition of ethyl acetate and washing with water, theorganic layer was dried over anhydrous sodium sulfate. After filtration,the filtrate was concentrated under reduced pressure.

The residue was dissolved in dichloromethane (5 ml), followed by theaddition of 3-chloroperbenzoic acid (214 mg, 1.24 mmol) at 0° C. Themixture was stirred at room temperature for 2 hours. The reactionmixture was washed with a 1N aqueous solution of sodium hydroxide andthen, the organic layer was dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was subjected to flash silica gel chromatography, and thefraction obtained from the hexane:ethyl acetate=2:1 eluate wasconcentrated under reduced pressure. The resulting solid was washed withdiethyl ether and then, collected by filtration, whereby the titlecompound (187 mg, 0.43 mmol, 69%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.40-1.57 (2H, m), 1.84-1.98 (2H, m),2.11-2.22 (1H, m), 2.50-2.60 (1H, m), 2.89 (3H, s), 2.93-3.02 (2H, m),4.48 (1H, dd, J=10.4, 3.8 Hz), 6.82-6.91 (1H, m), 7.00-7.07 (1H, m),7.24-7.29 (1H, m), 7.38 (1H, d, J=8.3 Hz), 7.79 (1H, dd, J=8.3, 2.4 Hz),8.48 (1H, d, J=2.4 Hz).

IR (ATR) cm⁻¹: 3059, 1566, 1495, 1446, 1279, 1161, 1107, 829.

Anal. Calcd for C₁₇H₁₈ClF₂NO₄S₂: C, 46.63; H, 4.14; Cl, 8.10; F, 8.68;N, 3.20; S, 14.64. Found: C, 46.36; H, 4.29; Cl, 8.08; F, 8.65; N, 3.25;S, 14.57.

MS m/z: 438 (M⁺+H).

Example 1792-[1-(Cyclohexylsulfonyl)-5-(methylsulfonyl)pentyl]-1,4-difluorobenzene

To a dichloromethane (3 ml) solution of the1-(2,5-difluorophenyl)-5-(methylsulfonyl)-1-pentanol (100 mg, 0.36 mmol)obtained in Referential Example 30 were successively added triethylamine(0.072 ml, 0.52 mmol) and methanesulfonyl chloride (0.033 ml, 0.43 mmol)at 0° C. The resulting mixture was stirred at room temperature for 1hour. The reaction mixture was washed with a saturated aqueous solutionof sodium bicarbonate. The organic layer was dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure.

To an acetonitrile (3 ml) solution of the resulting residue weresuccessively added cyclohexanethiol (0.066 ml, 0.54 mmol) and cesiumcarbonate (176 mg, 0.54 mmol). The resulting mixture was stirred at roomtemperature for 2 hours. The reaction mixture added with dichloromethanewas washed with brine and then, the organic layer was dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected to flashsilica gel chromatography, and the fraction obtained from thehexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure.

The residue was dissolved in dichloromethane (3 ml), followed by theaddition of 3-chloroperbenzoic acid (113 mg, 0.43 mmol) at 0° C. and themixture was stirred at room temperature for 2 hours. The reactionmixture was washed with a 1N aqueous solution of sodium hydroxide andthen, the organic layer was dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was subjected to flash silica gel chromatography, and thefraction obtained from the hexane:ethyl acetate=3:2 eluate wasconcentrated under reduced pressure. The resulting solid was washed withdiethyl ether and collected by filtration, whereby the title compound(53 mg, 0.13 mmol, 36%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.03-1.27 (3H, m), 1.30-1.70 (5H, m),1.78-2.10 (7H, m), 2.40-2.60 (2H, m), 2.88 (3H, s), 2.90-3.02 (2H, m),4.54 (1H, dd, J=11.1, 2.6 Hz), 7.04-7.15 (2H, m), 7.36-7.42 (1H, m).

IR (ATR) cm⁻¹: 2931, 1495, 1273, 1126, 1117, 976.

Anal. Calcd for C₁₈H₂₆F₂O₄S₂: C, 52.92; H, 6.41; F, 9.30; S, 15.70.Found: C, 52.85; H, 6.31; F, 9.34; S, 15.53.

MS m/z: 409 (M⁺+H).

Example 1804-[4-[[1-(2,5-Difluorophenyl)-5-(methylsulfonyl)pentyl]sulfonyl]phenyl]morpholine

To a dimethylsulfoxide (0.5 ml) solution of the1,4-difluoro-2-[1-[(4-fluorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene(40 mg, 0.095 mmol) obtained in Example 160 were successively addedmorpholine (0.012 ml, 0.14 mmol) and 1-methylpiperidine (0.017 ml, 0.14mmol). The resulting mixture was allowed to stand at 80° C. for 24hours. The reaction mixture was purified by preparative high performanceliquid chromatography (using a mixed solvent ofwater/acetonitrile/formic acid). The resulting solid was washed withdiethyl ether and collected by filtration, whereby the title compound(43 mg, 0.088 mmol, 92%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.31-1.51 (2H, m), 1.77-1.94 (2H, m),2.02-2.14 (1H, m), 2.38-2.50 (1H, m), 2.88 (3H, s), 2.90-3.00 (2H, m),3.28 (4H, t, J=4.9 Hz), 3.85 (4H, t, J=4.9 Hz), 4.47 (1H, dd, J=10.6,3.5 Hz), 6.78 (2H, d, J=9.0 Hz), 6.83-6.90 (1H, m), 6.94-7.01 (1H, m),7.19-7.24 (1H, m), 7.44 (2H, d, J=9.0 Hz).

IR (ATR) cm⁻¹: 2962, 1591, 1498, 1271, 1131, 1090, 976, 926.

Anal. Calcd for C₂₂H₂₇F₂NO₅S₂: C, 54.19; H, 5.58; F, 7.79; N, 2.87; S,13.15. Found: C, 53.93; H, 5.53; F, 7.90; N, 2.87; S, 13.17.

MS m/z: 488 (M⁺+H).

Example 1811-[4-[[1-(2,5-Difluorophenyl)-5-(methylsulfonyl)pentyl]sulfonyl]phenyl]piperidine

In a similar manner to Example 180 except for the use of1,4-difluoro-2-[1-[(4-fluorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene(100 mg, 0.24 mmol) and piperidine (0.035 ml, 0.36 mmol), the titlecompound (83 mg, 0.17 mmol, 71%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.30-1.51 (2H, m), 1.56-1.72 (6H, m),1.76-1.93 (2H, m), 2.01-2.13 (1H, m), 2.36-2.48 (1H, m), 2.87 (3H, s),2.88-3.00 (2H, m), 3.34 (4H, br s), 4.45 (1H, dd, J=11.5, 3.4 Hz), 6.75(2H, d, J=9.0 Hz), 6.82-6.90 (1H, m), 6.92-7.00 (1H, m), 7.16-7.23 (1H,m), 7.38 (2H, d, J=9.0 Hz).

IR (ATR) cm⁻¹: 2935, 1591, 1495, 1282, 1122, 1090.

Anal. Calcd for C₂₃H₂₉F₂NO₄S₂: C, 56.89; H, 6.02; F, 7.82; N, 2.88; S,13.21. Found: C, 56.73; H, 5.99; F, 7.88; N, 2.93; S, 13.22.

MS m/z: 486 (M⁺+H).

Example 1824-[1-(2,5-Difluorophenyl)-5-methylsulfonylpentylsulfonyl]-N,N-dimethylaniline

In a similar manner to Example 180 except for the use of1,4-difluoro-2-[1-[(4-fluorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene(100 mg, 0.24 mmol) and dimethylamine hydrochloride (58 mg, 0.71 mmol),the title compound (83 mg, 0.19 mmol, 78%) was obtained as a whitepowder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.30-1.50 (2H, m), 1.76-1.93 (2H, m),2.01-2.12 (1H, m), 2.36-2.48 (1H, m), 2.87 (3H, s), 2.88-3.00 (2H, m),3.03 (6H, s), 4.45 (1H, dd, J=11.2, 2.9 Hz), 6.55 (2H, d, J=9.0 Hz),6.82-6.91 (1H, m), 6.93-7.01 (1H, m), 7.18-7.24 (1H, m), 7.38 (2H, d,J=9.0 Hz).

IR (ATR) cm⁻¹: 2941, 1603, 1496, 1284, 1269, 1230, 1138, 1088.

Anal. Calcd for C₂₀H₂₅F₂NO₄S₂: C, 53.91; H, 5.66; F, 8.53; N, 3.14; S,14.39. Found: C, 53.61; H, 5.61; F, 8.51; N, 3.06; S, 14.35.

MS m/z: 446 (M⁺+H).

Example 1831-[4-[[1-(2,5-Difluorophenyl)-5-(methylsulfonyl)pentyl]sulfonyl]phenyl]-4-methylpiperazine

In a similar manner to Example 180 except for the use of1,4-difluoro-2-[1-[(4-fluorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene(100 mg, 0.24 mmol) and 1-methylpiperazine (0.040 ml, 0.36 mmol), thetitle compound (68 mg, 0.14 mmol, 57%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.31-1.51 (2H, m), 1.77-1.94 (2H, m),2.02-2.13 (1H, m), 2.35 (3H, s), 2.36-2.48 (1H, m), 2.53 (4H, t, J=5.1Hz), 2.87 (3H, s), 2.88-3.00 (2H, m), 3.34 (4H, t, J=5.1 Hz), 4.46 (1H,dd, J=11.0, 3.7 Hz), 6.77 (2H, d, J=9.0 Hz), 6.82-6.90 (1H, m),6.92-7.01 (1H, m), 7.18-7.23 (1H, m), 7.41 (2H, d, J=9.0 Hz).

IR (ATR) cm⁻¹: 1595, 1495, 1292, 1134, 1090, 1003, 968.

Anal. Calcd for C₂₃H₃₀F₂N₂O₄S₂: C, 55.18; H, 6.04; F, 7.59; N, 5.60; S,12.81. Found: C, 54.92; H, 5.92; F, 7.66; N, 5.60; S, 12.80.

MS m/z: 501 (M⁺+H).

Example 184N-Benzyl-4-[1-(2,5-difluorophenyl)-5-methylsulfonylpentylsulfonyl]-N-methylaniline

In a similar manner to Example 180 except for the use of1,4-difluoro-2-[1-[(4-fluorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene(100 mg, 0.24 mmol) and N-benzylmethylamine (0.046 ml, 0.36 mmol), thetitle compound (34 mg, 0.065 mmol, 27%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.30-1.50 (2H, m), 1.76-1.93 (2H, m),2.01-2.13 (1H, m), 2.36-2.48 (1H, m), 2.87 (3H, s), 2.88-3.00 (2H, m),3.11 (3H, s), 4.46 (1H, dd, J=11.4, 3.5 Hz), 4.58 (1H, d, J=17.5 Hz),4.63 (1H, d, J=17.5 Hz), 6.60 (2H, d, J=9.0 Hz), 6.78-6.86 (1H, m),6.89-6.98 (1H, m), 7.12 (2H, d, J=7.1 Hz), 7.13-7.20 (1H, m), 7.24-7.35(3H, m), 7.35 (2H, d, J=9.0 Hz).

IR (ATR) cm⁻¹: 1593, 1493, 1390, 1281, 1124, 1088.

Anal. Calcd for C₂₆H₂₉F₂NO₄S₂: C, 59.86; H, 5.60; F, 7.28; N, 2.69; S,12.29. Found: C, 59.74; H, 5.52; F, 7.35; N, 2.76; S, 12.44.

MS m/z: 522 (M⁺+H).

Example 185N-Benzyl-4-[1-(2,5-difluorophenyl)-5-methylsulfonylpentylsulfonyl]aniline

In a similar manner to Example 180 except for the use of1,4-difluoro-2-[1-[(4-fluorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene(100 mg, 0.24 mmol) and benzylamine (0.039 ml, 0.36 mmol), the titlecompound (49 mg, 0.097 mmol, 41%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.31-1.50 (2H, m), 1.78-1.93 (2H, m),2.01-2.13 (1H, m), 2.37-2.48 (1H, m), 2.87 (3H, s), 2.89-3.00 (2H, m),4.36 (2H, br d, J=3.7 Hz), 4.46 (1H, dd, J=11.2, 3.2 Hz), 4.61 (1H, brs), 6.51 (2H, d, J=9.0 Hz), 6.80-6.87 (1H, m), 6.90-6.98 (1H, m),7.15-7.22 (1H, m), 7.29-7.40 (5H, m), 7.34 (2H, d, J=9.0 Hz).

IR (ATR) cm⁻¹: 3411, 1597, 1495, 1282, 1142, 1086, 870.

Anal. Calcd for C₂₅H₂₇F₂NO₄S₂.0.25H₂O: C, 58.63; H, 5.41; F, 7.42; N,2.74; S, 12.52. Found: C, 58.59; H, 5.27; F, 7.49; N, 2.78; S, 12.61.

MS m/z: 508 (M⁺+H).

Referential Example 346-(t-Butyl-diphenylsilyloxy)-1-(2,5-difluorophenyl)-1-hexanol

A tetrahydrofuran (30 ml) solution of 1-bromo-2,5-difluorobenzene (0.956ml, 8.46 mmol) was stirred at −78° C. To the reaction mixture was addeda hexane solution (6.46 ml, 10.2 mmol) of n-butyl lithium. The reactionmixture was added to a tetrahydrofuran (20 ml) solution of6-(t-butyldiphenylsilyloxy)hexanal (2.50 g, 7.05 mmol) at −78° C. andthe mixture was stirred at the same temperature for 30 minutes. Afterthe temperature of the reaction mixture was elevated to roomtemperature, diethyl ether was added thereto. The mixture was washedwith a saturated aqueous solution of ammonium chloride and the organiclayer was dried over anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The residue wassubjected to flash silica gel chromatography, and the fraction obtainedfrom the hexane:ethyl acetate=9:1 eluate was concentrated under reducedpressure, whereby the title compound (2.92 g, 4.65 mmol, 88%) wasobtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.04 (9H, m), 1.21-1.90 (8H, m), 3.64 (2H, t,J=6.3 Hz), 4.96 (1H, t, J=6.5 Hz), 6.86-7.01 (2H, m), 7.13-7.20 (1H, m),7.32-7.45 (6H, m), 7.62-7.70 (4H, m).

Example 1866-[(5-Chloro-2-pyridyl)sulfonyl]-(2,5-difluorophenyl)-1-hexanol

To a dichloromethane (20 ml) solution of6-(t-butyldiphenylsilyl)oxy-1-(2,5-difluorophenyl)-1-hexanol (1.04 g,2.22 mmol) were successively added triethylamine (0.619 ml, 4.44 mmol)and methanesulfonyl chloride (0.258 ml, 3.33 mmol) at 0° C. The mixturewas stirred at room temperature for 2 hours. The reaction mixture waswashed with a saturated aqueous solution of sodium bicarbonate and theorganic layer was dried over anhydrous sodium sulfate. After filtration,the filtrate was concentrated under reduced pressure.

To an N,N-dimethylformamide (20 ml) solution of the residue weresuccessively added the 5-chloro-2-pyridinethiol (323 mg, 2.22 mmol)obtained in Referential Example 32 and potassium carbonate (368 mg, 2.66mmol). The mixture was stirred at room temperature for 3 hours. Ethylacetate was added to the reaction mixture. After washing with water, theorganic layer was dried over anhydrous sodium sulfate. After filtration,the filtrate was concentrated under reduced pressure.

The residue thus obtained was dissolved in dichloromethane (20 ml) andat 0° C., 3-chloroperbenzoic acid (1.18 g, 4.44 mmol) was added to theresulting solution. The mixture was stirred at room temperature for 3hours. The reaction mixture was washed with a 1N aqueous solution ofsodium hydroxide. The organic layer was then dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure.

A tetrahydrofuran (10 ml) solution of the residue was added with atetrahydrofuran solution (3.33 ml, 3.33 mmol) of tetrabutylammoniumfluoride, and the mixture was stirred at room temperature for 8 hours.After concentration of the reaction mixture under reduced pressure, theresidue was dissolved in ethyl acetate, followed by washing with water.The organic layer was dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was subjected to flash silica gel chromatography and thefraction obtained from the hexane:ethyl acetate=7:3 eluate wasconcentrated under reduced pressure, whereby the title compound (477 mg,1.22 mmol, 55%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.17-1.59 (6H, m), 2.04-2.17 (1H, m),2.30-2.42 (1H, m), 3.59 (2H, t, J=6.3 Hz), 5.07 (1H, dd, J=11.6, 2.8Hz), 6.84-6.92 (1H, m), 6.93-7.01 (1H, m), 7.26-7.32 (1H, m), 7.74 (1H,dd, J=8.3, 0.7 Hz), 7.78 (1H, dd, J=8.3, 2.2 Hz), 8.67 (1H, dd, J=2.2,0.7 Hz).

MS m/z: 390 (M⁺+H).

Example 1875-Chloro-2-[[1-(2,15-difluorophenyl)cyclohexyl]sulfonyl]pyridine

To a toluene (5 ml) solution of6-[(5-chloro-2-pyridyl)sulfonyl]-(2,5-difluorophenyl)-1-hexanol (308 mg,0.79 mmol) was added a toluene (3 ml) solution ofcyanomethylenetri-n-butylphosphorane (424 mg, 1.58 mmol). The resultingmixture was heated under reflux for 16 hours. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The residue thus obtained was subjected to flashchromatography on a silica gel column and the fraction obtained from thehexane:ethyl acetate=9:1 eluate was concentrated under reduced pressure.The resulting solid was washed with diethyl ether and then collected byfiltration, whereby the title compound (96 mg, 0.26 mmol, 33%) wasobtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.12-1.42 (3H, m), 1.58-1.66 (1H, m),1.77-1.86 (2H, m), 2.11-2.25 (2H, m), 2.91 (2H, br s), 6.79-6.89 (1H,m), 6.97-7.04 (1H, m), 7.06-7.13 (1H, m), 7.50 (1H, d, J=8.3 Hz), 7.72(1H, dd, J=8.3, 2.4 Hz), 8.65 (1H, dd, J=2.4 Hz).

IR (ATR) cm⁻¹: 2933, 2862, 1493, 1302, 1190, 1153, 1107, 1012.

Anal. Calcd for C₁₇H₁₆ClF₂NO₂S: C, 54.91; H, 4.34; Cl, 9.53; F, 10.22;N, 3.77; S, 8.62. Found: C, 54.88; H, 4.50; Cl, 9.65; F, 10.35; N, 3.80;S, 8.76.

MS m/z: 372 (M⁺+H).

Referential Example 357-(t-Butyldiphenylsilyloxy)-1-(2,5-difluorophenyl)-1-heptanol

A tetrahydrofuran (40 ml) solution of 1-bromo-2,5-difluorobenzene (1.21ml, 10.7 mmol) was stirred at −78° C., followed by the addition of ahexane solution (8.50 ml, 13.4 mmol) of n-butyl lithium. The reactionmixture was added to a tetrahydrofuran (20 ml) solution of7-(t-butyldiphenylsilyloxy)heptanal (3.28 g, 8.90 mmol) at −78° C. andthe mixture was stirred at the same temperature for 30 minutes. Afterthe temperature of the reaction mixture was elevated to roomtemperature, diethyl ether was added thereto. The mixture was washedwith a saturated aqueous solution of ammonium chloride. The organiclayer was then dried over anhydrous sodium sulfate. After filtration,the filtrate was concentrated under reduced pressure. The residue wassubjected to flash silica gel chromatography, and the fraction obtainedfrom the hexane:ethyl acetate=9:1 eluate was concentrated under reducedpressure, whereby the title compound (3.88 g, 8.04 mmol, 90%) wasobtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.04 (9H, m), 1.21-1.92 (10H, m), 3.64 (2H,t, J=6.5 Hz), 4.97 (1H, t, J=6.5 Hz), 6.86-7.00 (2H, m), 7.13-7.20 (1H,m), 7.33-7.44 (6H, m), 7.62-7.70 (4H, m).

Example 1887-[(5-Chloro-2-pyridyl)sulfonyl]-(2,5-difluorophenyl)-1-heptanal

To a dichloromethane (20 ml) solution of7-(t-butyldiphenylsilyloxy)-1-(2,5-difluorophenyl)-1-heptanol (1.04 g,2.15 mmol) were successively added triethylamine (0.601 ml, 4.31 mmol)and methanesulfonyl chloride (0.250 ml, 3.23 mmol) at 0° C. Theresulting mixture was stirred at room temperature for 2 hours. Thereaction mixture was washed with a saturated aqueous solution of sodiumbicarbonate and then, the organic layer was dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure.

To an N,N-dimethylformamide (20 ml) solution of the residue weresuccessively added the 5-chloro-2-pyridinethiol (314 mg, 2.15 mmol)obtained in Referential Example 32 and potassium carbonate (357 mg, 2.59mmol) and the resulting mixture was stirred at room temperature for 3hours. Ethyl acetate was added and the mixture was washed with water.The organic layer was then dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure.

To a dichloromethane (20 ml) solution of the resulting residue was added3-chloroperbenzoic acid (1.14 g, 4.31 mmol) at 0° C. and the mixture wasstirred at room temperature for 2 hours. The reaction mixture was washedwith a 1N aqueous solution of sodium hydroxide. The organic layer wasthen dried over anhydrous sodium sulfate. After filtration, the filtratewas concentrated under reduced pressure.

The resulting residue was dissolved in tetrahydrofuran (10 ml), followedby the addition of a tetrahydrofuran solution (3.23 ml, 3.23 mmol) oftetrabutylammonium fluoride. The resulting mixture was stirred at roomtemperature for 8 hours. After concentration of the reaction mixtureunder reduced pressure, the residue was dissolved in ethyl acetate andthe solution was washed with water. The organic layer was dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected to flashsilica gel chromatography, and the fraction obtained from thehexane:ethyl acetate=7:3 eluate was concentrated under reduced pressure,whereby the title compound (595 mg, 1.47 mmol, 69%) was obtained as acolorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.14-1.66 (8H, m), 2.03-2.17 (1H, m),2.29-2.40 (1H, m), 3.60 (2H, t, J=6.6 Hz), 5.06 (1H, dd, J=11.6, 3.1Hz), 6.84-6.91 (1H, m), 6.92-7.00 (1H, m), 7.25-7.31 (1H, m), 7.74 (1H,dd, J=8.3 Hz), 7.78 (1H, dd, J=8.3, 2.2 Hz), 8.67 (1H, dd, J=2.2 Hz).

MS m/z: 404 (M⁺+H).

Example 1895-Chloro-2-[[1-(2,5-difluorophenyl)cycloheptyl]sulfonyl]pyridine

To a toluene (8 ml) solution of7-[(5-chloro-2-pyridyl)sulfonyl]-(2,5-difluorophenyl)-1-heptanol (436mg, 1.08 mmol) was added a toluene (3 ml) solution ofcyanomethylenetri-n-butylphosphorane (579 mg, 2.16 mmol). The resultingmixture was heated under reflux for 16 hours. The reaction mixture wascooled to room temperature and then, was concentrated under reducedpressure. The residue thus obtained was subjected to flashchromatography on a silica gel column and the fraction obtained from thehexane:ethyl acetate=9:1 eluate was concentrated under reduced pressure.The resulting solid was washed with diethyl ether and then collected byfiltration, whereby the title compound (79 mg, 0.20 mmol, 19%) wasobtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.32-1.63 (6H, m), 1.82-1.94 (2H, m),2.42-2.52 (2H, m), 2.79-2.90 (2H, m), 6.81-6.90 (1H, m), 6.97-7.07 (2H,m), 7.48 (1H, d, J=8.6 Hz), 7.71 (1H, dd, J=8.6, 2.5 Hz), 8.65 (1H, dd,J=2.5 Hz).

IR (ATR) cm⁻¹: 2933, 2864, 1493, 1308, 1188, 1159, 1107, 1011.

Anal. Calcd for C₁₈H₁₈ClF₂NO₂S: C, 56.03; H, 4.70; Cl, 9.19; F, 9.85; N,3.63; S, 8.31. Found: C, 55.92; H, 4.77; Cl, 9.23; F, 9.90; N, 3.67; S,8.41.

MS m/z: 386 (M⁺+H).

Referential Example 36 2,5-Difluorophenyl-4-pyridylmethanol

A tetrahydrofuran (30 ml) solution of 1-bromo-2,5-difluorobenzene (1.08ml, 9.60 mmol) was stirred at −78° C., followed by the addition of ahexane solution (7.32 ml, 11.5 mmol) of n-butyl lithium. To theresulting mixture was added a tetrahydrofuran (10 ml) solution of4-pyridinecarboxyaldehyde (0.764 ml, 8.00 mmol) at −78° C. and themixture was stirred at the same temperature for 30 minutes. After thetemperature of the reaction mixture was raised to room temperature,diethyl ether was added thereto. The mixture was washed with a saturatedaqueous solution of sodium bicarbonate. The organic layer was then driedover anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was subjected to flashsilica gel chromatography, and the fraction obtained from thehexane:ethyl acetate=7:3 eluate was concentrated under reduced pressure.The resulting solid was washed with diisopropyl ether and then collectedby filtration, whereby the title compound (1.15 g, 5.20 mmol, 65%) wasobtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 4.25 (1H, br s), 6.09 (1H, s), 6.89-7.05 (2H,m), 7.14-7.23 (1H, m), 7.34 (2H, d, J=5.4 Hz), 8.44 (2H, d, J=5.4 Hz).

Example 1905-Chloro-2-[(2,5-difluorophenyl-4-pyridylmethyl)thio]pyridine

To a dichloromethane (10 ml) solution of2,5-difluorophenyl-4-pyridylmethanol (221 mg, 1.00 mmol) weresuccessively added triethylamine (0.279 ml, 2.00 mmol) andmethanesulfonyl chloride (0.116 ml, 1.50 mmol) at 0° C. The resultingmixture was stirred at room temperature for 3 hours. The reactionmixture was washed with a saturated aqueous solution of sodiumbicarbonate and then, the organic layer was dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure.

To an N,N-dimethylformamide (10 ml) solution of the resulting residuewere successively added 5-chloro-2-pyridinethiol (145 mg, 1.00 mmol)obtained in Referential Example 32 and potassium carbonate (166 mg, 1.20mmol). The resulting mixture was stirred at room temperature for 2hours. Ethyl acetate was added and the mixture was washed with water.The organic layer was then dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was subjected to flash silica gel chromatography and thefraction obtained from the hexane:ethyl acetate=17:3 eluate wasconcentrated under reduced pressure, whereby the title compound (267 mg,0.77 mmol, 77%) was obtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.52 (1H, s), 6.92-6.98 (1H, m), 6.99-7.06(1H, m), 7.48 (1H, dd, J=8.5, 0.7 Hz), 7.17-7.23 (1H, m), 7.34 (2H, d,J=6.1 Hz), 7.47 (1H, dd, J=8.5, 2.4 Hz), 8.33 (1H, dd, J=2.4, 0.7 Hz),8.54 (2H, d, J=6.1 Hz).

MS m/z: 349 (M⁺+H).

Example 1915-Chloro-2-[(2,5-difluorophenyl-4-pyridylmethyl)sulfonyl]pyridine

To a methanol (6 ml) solution of5-chloro-2-[(2,5-difluorophenyl-4-pyridylmethyl)thio]pyridine (239 mg,0.68 mmol) was added a water (12 ml) solution of Oxone (potassiumperoxymonosulfate compound, 2KHSO₅.KHSO₄.K₂SO₄) (631 mg, 1.03 mmol) at0° C. After stirring at room temperature for 3 days, to the reactionmixture was added dichloromethane and the mixture was washed with asaturated aqueous solution of sodium bicarbonate. The organic layer wasdried over anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified bypreparative high performance liquid chromatography (using a mixedsolvent of water/acetonitrile/formic acid). The resulting solid waswashed with hexane/diisopropyl ether and then, collected by filtration,whereby the title compound (67 mg, 0.18 mmol, 26%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 6.44 (1H, s), 6.96-7.08 (2H, m), 7.48 (2H, d,J=6.3 Hz), 7.70-7.77 (1H, m), 7.79 (1H, dd, J=8.3, 2.2 Hz), 7.84 (1H,dd, J=8.3, 0.7 Hz), 8.61 (2H, d, J=6.3 Hz), 8.67 (1H, dd, J=2.2, 0.7Hz).

IR (ATR) cm⁻¹: 1591, 1493, 1329, 1161, 1107, 1014.

Anal. Calcd for C₁₇H₁₁ClF₂N₂O₂S: C, 53.62; H, 2.91; F, 9.98; N, 7.36; S,8.42. Found: C, 53.55; H, 2.87; F, 10.10; N, 7.40; S, 8.55.

MS m/z: 381 (M⁺+H).

Example 192 5-(4-Chlorobenzenesulfonylmethyl)-1H-tetrazole

To an N,N-dimethylformamide (100 ml) solution of4-chlorophenylsulfonylacetonitrile (2.81 g, 13.0 mmol) and triethylaminehydrochloride (4.24 g, 65.2 mmol) was added sodium azide (10.8 g, 78.2mmol) and the mixture was stirred at 80° C. for 16 hours. The reactionmixture was then cooled to room temperature. Ethyl acetate was added andthe mixture was washed with a saturated aqueous solution of ammoniumchloride. The organic layer was dried over anhydrous sodium sulfate.After filtration, the filtrate was concentrated under reduced pressure.The resulting solid was washed with diethyl ether and then, collected byfiltration, whereby the title compound (2.53 g, 9.78 mmol, 75%) wasobtained as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 5.02 (2H, s), 7.62 (1H, d, J=8.6 Hz), 7.73(2H, d, J=8.6 Hz).

MS m/z: 300 (M⁺+H+CH₃CN).

Example 193 1-Benzyl-5-(4-chlorobenzenesulfonylmethyl)-1H-tetrazole(Isomer 193-A) and2-benzyl-5-(4-chlorobenzenesulfonylmethyl)-2H-tetrazole (Isomer 193-B)

To a dichloromethane/tetrahydrofuran (1:1) (20 ml) solution of5-(4-chlorophenylsulfonylmethyl)-1H-tetrazole (837 mg, 3.24 mmol) andbenzyl alcohol (0.335 ml, 3.24 mmol) was added triphenylphosphine (849mg, 3.24 mmol) under ice cooling. Then, diethyl azodicarboxylate (0.510ml, 3.24 mmol) was added dropwise at the same temperature. The reactionmixture was stirred at room temperature for 16 hours, followed byconcentration under reduced pressure. The residue was subjected to flashsilica gel chromatography and the fraction obtained from thehexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure,whereby the title Isomer 193-A (406 mg, 1.16 mmol, 36%) and the titleIsomer 193-B (317 mg, 0.91 mmol, 28%) were obtained, each as a whitesolid.

Based on the NOE (Nuclear Overhauser Effect) test, the structure of eachof Isomer 193-A and Isomer 193-B was determined.

Isomer 193-A

¹H-NMR (400 MHz, CDCl₃) δ: 4.46 (2H, s), 5.88 (2H, s), 7.22-7.43 (5H,m), 7.51 (2H, d, J=8.7 Hz), 7.57 (2H, d, J=8.7 Hz).

MS m/z: 349 (M⁺+H).

Isomer 193-B

¹H-NMR (400 MHz, CDCl₃) δ: 4.68 (2H, s), 5.72 (2H, s), 7.22-7.45 (5H,m), 7.33 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz).

MS m/z: 349 (M⁺+H).

Example 1946-(1-Benzyl-1H-tetrazol-5-yl)-6-[(4-chlorophenyl)sulfonyl]-1-hexanol

To a toluene (5 ml) solution of1-benzyl-5-(4-chlorobenzenesulfonylmethyl)-1H-tetrazole (Isomer 193-A)(174 mg, 0.50 mmol) and 5-(t-butyldimethylsilyloxy)-1-pentanol (146 mg,0.60 mmol) was added cyanomethylenetri-n-butylphosphorane (161 mg, 0.60mmol). The resulting mixture was heated under reflux for 8 hours. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue was subjected to flash silica gelchromatography and the fraction obtained from the hexane:ethylacetate=87:13 eluate was concentrated under reduced pressure.

The residue was dissolved in tetrahydrofuran (5 ml), followed by theaddition of a tetrahydrofuran solution (0.410 ml, 0.41 mmol) oftetra-n-butylammonium fluoride. The resulting mixture was stirred atroom temperature for 4 hours. After concentration of the reactionmixture under reduced pressure, ethyl acetate was added to the residue.The mixture was washed with a saturated aqueous solution of ammoniumchloride. The organic layer was dried over anhydrous sodium sulfate.After filtration, the filtrate was concentrated under reduced pressure.The residue was subjected to flash silica gel chromatography and thefraction obtained from the hexane:ethyl acetate=1:1 eluate wasconcentrated under reduced pressure, whereby the title compound (115 mg,0.26 mmol, 54%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.54-0.67 (1H, m), 0.79-1.02 (3H, m), 1.08(1H, t, J=5.9 Hz), 1.19-1.32 (2H, m), 1.94-2.05 (1H, m), 2.06-2.16 (1H,m), 3.43 (2H, q, J=5.9 Hz), 4.21 (1H, dd, J=11.5, 3.4 Hz), 5.72 (1H, d,J=15.5 Hz), 6.04 (1H, d, J=15.5 Hz), 7.21-7.28 (2H, m), 7.37-7.44 (3H,m), 7.42 (2H, d, J=8.5 Hz), 7.50 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3402, 2935, 1581, 1456, 1321, 1151, 1084, 1012, 725.

MS m/z: 435 (M⁺+H).

FAB-MS: 435.1240 (Calcd for C₂₀H₂₄ClN₄O₃S: 435.1258).

Example 1951-Benzyl-5-[1-(4-chlorobenzenesulfonyl)cyclohexyl]-1H-tetrazole

To a toluene (3 ml) solution of6-(1-benzyl-1H-tetrazol-5-yl)-6-[(4-chlorophenyl)sulfonyl]-1-hexanol(104 mg, 0.24 mmol) was added a toluene (2 ml) solution ofcyanomethylenetri-n-butylphosphorane (128 mg, 0.48 mmol). The resultingmixture was heated under reflux for 7 hours. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The residue was subjected to flash silica gel chromatographyand the fraction obtained from the hexane:ethyl acetate=4:1 eluate wasconcentrated under reduced pressure. The resulting solid was washed withhexane/diethyl ether and then, collected by filtration, whereby thetitle compound (51 mg, 0.12 mmol, 51%) was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.45-0.93 (2H, m), 1.07-1.21 (1H, m),1.31-1.50 (3H, m), 2.07-2.20 (2H, m), 2.58-2.68 (2H, m), 6.13 (2H, s),7.21 (2H, d, J=8.8 Hz), 7.28-7.39 (5H, m), 7.41 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 2941, 1574, 1460, 1392, 1302, 1282, 1142, 1080, 1011,831.

MP: 154-155° C.

Anal. Calcd for C₂₀H₂₁ClN₄O₂S: C, 57.62; H, 5.08; Cl, 8.50; N, 13.44.Found: C, 57.47; H, 5.07; Cl, 8.53; N, 13.45.

MS m/z: 417 (M⁺+H).

Example 1966-(2-Benzyl-2H-tetrazol-5-yl)-6-[(4-chlorophenyl)sulfonyl]-1-hexanol

To a toluene (5 ml) solution of the2-benzyl-5-(4-chlorobenzenesulfonylmethyl)-2H-tetrazole (Isomer 193-B)(174 mg, 0.50 mmol) obtained in Example 193 and5-(t-butyldimethylsilyloxy)-1-pentanol (146 mg, 0.60 mmol) was addedcyanomethylenetri-n-butylphosphorane (161 mg, 0.60 mmol). The resultingmixture was heated under reflux for 8 hours. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The residue was subjected to flash silica gel chromatographyand the fraction obtained from the hexane:ethyl acetate=17:3 eluate wasconcentrated under reduced pressure.

The residue thus obtained was dissolved in tetrahydrofuran (5 ml),followed by the addition of a tetrahydrofuran (0.574 ml, 0.57 mmol)solution of tetra-n-butylammonium fluoride and the mixture was stirredat room temperature for 4 hours. After concentration of the reactionmixture under reduced pressure, ethyl acetate was added to the residue.The resulting mixture was washed with a saturated aqueous solution ofammonium chloride. The organic layer was dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure. The residue was subjected to flash silica gel chromatographyand the fraction obtained from the hexane:ethyl acetate=1:1 eluate wasconcentrated under reduced pressure, whereby the title compound (155 mg,0.36 mmol, 71%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.12-1.64 (7H, m), 2.22-2.34 (1H, m),2.36-2.48 (1H, m), 3.56 (2H, br s), 4.21 (1H, dd, J=11.4, 3.8 Hz), 5.69(1H, d, J=14.4 Hz), 5.73 (1H, d, J=14.4 Hz), 7.20 (2H, d, J=8.3 Hz),7.28-7.48 (5H, m), 7.37 (2H, d, J=8.3 Hz).

IR (ATR) cm⁻¹: 3543, 2933, 1581, 1475, 1394, 1321, 1149, 1088, 1012,723.

MS m/z: 435 (M⁺+H)

FAB-MS: 435.1252 (Calcd for C₂₀H₂₄ClN₄O₃S: 435.1258).

Example 1972-Benzyl-5-[1-(4-chlorobenzenesulfonyl)cyclohexyl]-2H-tetrazole

To a toluene (3 ml) solution of6-(2-benzyl-2H-tetrazol-5-yl)-6-[(4-chlorophenyl)sulfonyl]-1-hexanol(145 mg, 0.33 mmol) was added a toluene (3 ml) solution ofcyanomethylenetri-n-butylphosphorane (179 mg, 0.67 mmol). The resultingmixture was heated under reflux for 7 hours. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The residue was subjected to flash silica gel chromatographyand the fraction obtained from the hexane:ethyl acetate-4:1 eluate wasconcentrated under reduced pressure. The resulting solid was washed withhexane/diethyl ether and collected by filtration, whereby the titlecompound (78 mg, 0.19 mmol, 56%) was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.99-1.14 (2H, m), 1.21-1.36 (1H, m),1.52-1.62 (1H, m), 1.75-1.82 (2H, m), 2.15-2.25 (2H, m), 2.69-2.76 (2H,m), 5.72 (2H, s), 7.07 (2H, d, J=8.8 Hz), 7.11 (2H, d, J=8.8 Hz),7.34-7.47 (5H, m).

IR (ATR) cm⁻¹: 2939, 1579, 1477, 1396, 1317, 1144, 1084, 1012, 756.

MP: 133-134° C.

Anal. Calcd for C₂₀H₂₁ClN₄O₂S: C, 57.62; H, 5.08; Cl, 8.50; N, 13.44.Found: C, 57.74; H, 5.14; Cl, 8.51; N, 13.37.

MS m/z: 417 (M⁺+H).

Example 1983-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)-1-(1-pyrrolidinyl)-1-propanone

In dichloromethane (6 ml) was dissolved the3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propionic acid (200mg, 0.554 mmol) obtained in Example 62. To the resulting solution wasadded thionyl chloride (162 μl, 2.22 mmol). The resulting mixture wasstirred at room temperature for 24 hours. The reaction mixture was thenconcentrated to dryness. The residue thus obtained was dissolved indichloromethane (6 ml) and to the resulting solution were addedpyrrolidine (185 μl, 2.22 mmol) and triethylamine (309 μl, 2.22 mmol).The resulting mixture was stirred at room temperature for 2 hours. Thereaction mixture was diluted with dichloromethane, washed successivelywith water, a saturated aqueous ammonium chloride solution and brine,dried over magnesium sulfate and then concentrated. The residue thusobtained was subjected to flash chromatography on a silica gel column,and the fraction obtained from the hexane:ethyl acetate=1:1 eluate wasconcentrated. The colorless solid thus obtained was recrystallized fromethyl acetate-hexane, whereby the title compound (192 mg, 0.463 mmol,84%) was obtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 1.80-1.90 (2H, m), 1.96-2.03 (2H, m), 3.06 (1H, dd,J=16.4, 9.8 Hz), 3.28-3.57 (5H, m), 5.25 (1H, dd, J=9.8, 3.7 Hz), 6.81(1H, td, J=9.1, 4.4 Hz), 6.91-6.98 (1H, m), 7.18 (1H, ddd, J=8.6, 5.4,3.2 Hz), 7.38 (2H, d, J=8.6 Hz), 7.53 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 2949, 1633, 1583, 1495, 1442, 1396, 1346, 1308, 1277,1211, 1147, 1014, 822, 769, 708, 615, 536, 472.

mp: 122-125° C.

MS m/z: 414 (M⁺+H).

FAB-MS: 414.0769 (Calcd for C₁₉H₁₉ClF₂NO₃S: 414.0742)

Anal. calcd for C₁₉H₁₈ClF₂NO₃S: C, 55.14; H, 4.38; Cl, 8.57; F, 9.18; N,3.38; S, 7.75. Found: C, 55.22; H, 4.50; Cl, 8.44; F, 9.00; N, 3.39; S,7.78.

Example 199 t-Butyl4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyrate

In N,N-dimethylformamide (4 ml) was dissolved the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (101 mg, 0.333mmol) obtained in Example 5. After addition thereto of t-butyl acrylate(146 μl, 1.00 mmol) and 1,8-diazabicyclo[5,4,0]undece-7-en (151 μl, 1.00mmol), stirring was conducted at room temperature for 1 week. Thereaction mixture was then concentrated. The residue thus obtained wassubjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate=4:1 eluate wasconcentrated, whereby the title compound (142 mg, 0.329 mmol, 99%) wasobtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.40 (9H, s), 2.10-2.20 (1H, m), 2.23-2.35(2H, m), 2.65-2.76 (1H, m), 4.67 (1H, dd, J=10.3, 4.4 Hz), 6.85 (1H, td,J=10.3, 4.4 Hz), 6.96-7.03 (1H, m), 7.24 (1H, ddd, J=8.6, 5.4, 3.2 Hz),7.40 (2H, d, J=8.3 Hz), 7.56 (2H, d, J=8.3 Hz).

IR (ATR) cm⁻¹: 2978, 1724, 1583, 1496, 1367, 1321, 1232, 1146, 1084,1014, 829, 756, 710, 642, 629, 555, 471.

MS m/z: 431 (M⁺+H).

FAB-MS: 431.0904 (Calcd for C₂₀H₂₂ClF₂O₄S: 431.0895)

Example 200 4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyricacid

To a dichloromethane solution (10 ml) of t-butyl4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyrate (1.25 g,3.33 mmol) was added trifluoroacetic acid (5 ml). The resulting mixturewas stirred at room temperature for 4 hours. The solid obtained byconcentrating the reaction mixture was recrystallized from ethylacetate, whereby the title compound (595 mg, 1.59 mmol, 48%) wasobtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 2.32-2.50 (3H, m), 2.71-2.81 (1H, m), 4.68(1H, dd, J=9.3, 4.9 Hz), 6.86 (1H, td, J=9.3, 4.4 Hz), 6.97-7.04 (1H,m), 7.21-7.27 (1H, m), 7.40 (2H, d, J=8.6 Hz), 7.56 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 2942, 1710, 1571, 1495, 1427, 1327, 1240, 1151, 1084,1012, 916, 831, 789, 752, 710, 636, 555, 528, 463, 417.

mp: 157-158° C.

MS m/z: 375 (M⁺+H).

Anal. calcd for C₁₆H₁₃ClF₂O₄S: C, 51.27; H, 3.50; Cl, 9.46; F, 10.14; S,8.56. Found: C, 51.18; H, 3.47; Cl, 9.45; F, 10.32; S, 8.60.

Example 2014-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-1-(1-pyrrolidinyl)-1-butanone

To a tetrahydrofuran solution (4 ml) of4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyric acid (150 mg,0.400 mmol) were added pyrrolidine (40.1 μl, 0.480 mmol), triethylamine(61.2 μl, 0.440 mmol), 4-dimethylaminopyridine (10.0 mg, 0.0820 mmol)and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (84.5mg, 0.440 mmol). The resulting mixture was stirred at room temperaturefor 18 hours. The solvent was distilled off. The residue thus obtainedwas dissolved in ethyl acetate. The resulting solution was washed with asaturated aqueous ammonium chloride solution and brine, dried overmagnesium sulfate and then, concentrated. The residue thus obtained wassubjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate=3:7 eluate wasconcentrated. The resulting solid was recrystallized from ethylacetate-hexane, whereby the title compound (97.0 mg, 0.227 mmol, 57%)was obtained as colorless plate crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.78-1.93 (4H, m), 2.20-2.43 (3H, m),2.69-2.78 (1H, m), 3.15-3.21 (1H, m), 3.25-3.30 (1H, m), 3.41 (2H, t,J=6.8 Hz), 4.84 (1H, dd, J=8.5, 5.6 Hz), 6.86 (1H, td, J=9.0, 4.6 Hz),6.95-7.02 (1H, m), 7.24 (1H, ddd, J=8.8, 5.6, 3.4 Hz), 7.40 (2H, d,J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3072, 2973, 2875, 1635, 1496, 1444, 1421, 1317, 1234,1173, 1146, 1082, 1011, 877, 760, 737, 619, 559, 509, 469.

mp: 134-135° C.

MS m/z: 428 (M⁺+H).

Anal. calcd for C₂₀H₂₀ClF₂NO₃S: C, 56.14; H, 4.71; Cl, 8.29; F, 8.88; N,3.27; S, 7.49. Found: C, 56.01; H, 4.68; Cl, 8.03; F, 8.64; N, 3.35; S,7.63.

Example 2025-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-1-valeric acid

Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57 Mhexane solution, 578 μl, 0.908 mmol) was added to a dimethoxyethanesolution (5 ml) of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (250 mg, 0.825mmol) obtained in Example 5. After the temperature of the reactionmixture was elevated to room temperature, it was cooled again to −78° C.Ethyl 4-bromobutyrate (142 mg, 0.990 mmol) was added and the mixture wasstirred at room temperature for 5 hours. Water was added to the reactionmixture, followed by extraction with dichloromethane. The extracts werecombined, washed with water and brine, dried over magnesium sulfate andthen, concentrated. The residue thus obtained was dissolved intetrahydrofuran (4 ml). An aqueous solution (2 ml) of lithium hydroxide(19.8 mg, 0.825 mmol) was added to the resulting solution. The mixturewas stirred at room temperature for 15 hours. After 1N hydrochloric acidwas added to make the mixture to acidic, it was extracted withdichloromethane. The extracts were combined, washed with brine, driedover magnesium sulfate and then concentrated. The resulting solid wasrecrystallized from ethyl acetate-hexane, whereby the title compound(139 mg, 0.357 mmol, 43%) was obtained as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.53-1.55 (2H, m), 2.12-2.23 (1H, m),2.32-2.54 (3H, m), 4.52 (1H, dd, J=−11.5, 3.7 Hz), 6.84 (1H, td, J=9.0,4.4 Hz), 6.96-7.02 (1H, m), 7.23-7.28 (1H, m), 7.38 (2H, d, J=8.3 Hz),7.53 (2H, d, J=8.3 Hz).

IR (ATR) cm⁻¹: 2945, 1693, 1585, 1495, 1427, 1323, 1296, 1238, 1211,1153, 1086, 1012, 949, 829, 750, 708, 628, 542, 463.

mp: 151-152° C.

MS m/z: 389 (M⁺+H).

Anal. calcd for C₁₇H₁₅ClF₂O₄S: C, 52.51; H, 3.89; Cl, 9.12; F, 9.77; S,8.25. Found: C, 52.36; H, 3.88; Cl, 9.14; F, 9.75; S, 8.37.

Example 2035-[(4-Chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-1-(1-pyrrolidinyl)-1-pentanone

Under an argon atmosphere and at −15° C., N-methylmorpholine (38.5 μl,0.351 mmol) and isobutyl chloroformate (45.8 μl, 0.351 mmol) were addedto a tetrahydrofuran solution (4 ml) of5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-1-valeric acid (130mg, 0.334 mmol). The mixture was stirred for 5 minutes at −15° C.Pyrrolidine (33.5 μl, 0.401 mmol) was added and the mixture was stirredat room temperature for 1 hour. The reaction mixture was diluted withdichloromethane, washed with a saturated aqueous ammonium chloridesolution and brine, dried over magnesium sulfate and then concentrated.The residue thus obtained was subjected to flash chromatography on asilica gel column, and the fraction obtained from the hexane:ethylacetate=1:2 eluate was concentrated. The resulting solid wasrecrystallized from ethyl acetate-hexane, whereby the title compound(128 mg, 0.290 mmol, 87%) was obtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.52-1.66 (2H, m), 1.80-1.88 (2H, m),1.91-1.98 (2H, m), 2.15-2.34 (3H, m), 2.41-2.50 (1H, m), 3.34 (2H, td,J=6.8, 2.4 Hz), 3.41 (2H, t, J=6.8 Hz), 4.55 (1H, dd, J=11.7, 2.9 Hz),6.81 (1H, td, J=9.0, 4.4 Hz), 6.93-7.00 (1H, m), 7.22-7.28 (1H, m), 7.38(2H, d, J=8.5 Hz), 7.52 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 2941, 2883, 1635, 1583, 1496, 1441, 1315, 1277, 1244,1215, 1180, 1146, 1082, 1038, 1014, 829, 787, 752, 710, 631, 548, 519,480, 440.

mp: 125-126° C.

MS m/z: 442 (M⁺+H).

Anal. calcd for C₂₁H₂₂ClF₂NO₃S: C, 57.07; H, 5.02; Cl, 8.02; F, 8.60; N,3.17; S, 7.26. Found: C, 57.04; H, 5.13; Cl, 8.03; F, 8.64; N, 3.29; S,7.39.

Referential Example 37 5-Bromo-1-(1-pyrrolildinyl)-1-pentanone

Under an argon atmosphere, N-methylmorpholine (606 μl, 5.52 mmol) andisobutyl chloroformate (757 μl, 5.80 mmol) were added to atetrahydrofuran solution (35 ml) of 6-bromovaleric acid (1.00 g, 5.52mmol) at −15° C. The resulting mixture was stirred for 5 minutes at −15°C. Pyrrolidine (484 μl, 5.80 mmol) was added and the resulting mixturewas stirred at −15° C. for 5 minutes and then, at room temperature for 1hour. Ice water was added and the mixture was extracted withdichloromethane. The extract was washed with brine, dried over magnesiumsulfate and then, concentrated. The residue thus obtained was subjectedto flash chromatography on a silica gel column, and the fractionobtained from the hexane:ethyl acetate=1:2 eluate was concentrated,whereby the title compound (1.18 g, 5.04 mmol, 91%) was obtained as acolorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.77-2.00 (8H, m), 2.29 (2H, t, J=7.3 Hz),3.39-3.48 (6H, m).

MS m/z: 234 (M⁺+H).

Example 2046-[(4-Chlorophenyl)sulfonyl]-6-(2,5-difluorophenyl)-1-hexanone

Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57 Mhexane solution, 701 μl, 1.10 mmol) was added to a dimethoxyethanesolution (6 ml) of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (303 mg, 1.00mmol) obtained in Example 5. After the temperature of the reactionmixture was elevated to room temperature, it was cooled again to −78° C.After addition of 5-bromo-1-(1-pyrrolidinyl)-1-pentanone (281 mg, 1.20mmol), the resulting mixture was stirred at room temperature for 20hours. The reaction mixture was added with water, and then, diluted withdichloromethane. The solution thus obtained was washed successively withwater and brine, dried over magnesium sulfate and then, concentrated.The residue thus obtained was subjected to flash chromatography on asilica gel column, and the fraction obtained from the hexane:ethylacetate=1:2 eluate was concentrated. The resulting solid wasrecrystallized from ethyl acetate-hexane, whereby the title compound(385 mg, 0.844 mmol, 84%) was obtained as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.25-1.37 (2H, m), 1.58-1.75 (2H, m),1.80-1.88 (2H, m), 1.91-1.97 (2H, m), 2.07-2.16 (1H, m), 2.20 (2H, td,J=7.6, 3.2 Hz), 2.41-2.50 (1H, m), 3.35 (2H, t, J=6.8 Hz), 3.43 (2H, t,J=6.8 Hz), 4.50-4.56 (1H, m), 6.83 (1H, td, J=9.0, 4.4 Hz), 6.94-7.01(1H, m), 7.24 (1H, ddd, J=8.8, 5.4, 3.2 Hz), 7.38 (2H, d, J=8.8 Hz),7.53 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 2952, 1626, 1493, 1441, 1321, 1232, 1149, 1086, 1014,820, 768, 631, 528, 469.

mp: 135-136° C.

MS m/z: 456 (M⁺+H).

Anal. calcd for C₂₂H₂₄ClF₂NO₃S: C, 57.95; H, 5.31; Cl, 7.78; F, 8.33; N,3.07; S, 7.03. Found: C, 57.73; H, 5.20; Cl, 7.76; F, 8.31; N, 3.13; S,7.14.

Example 205 7-[(4-Chlorophenyl)sulfonyl]-7-(2,5-difluorophenyl)heptanoicacid

Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57 Mhexane solution, 2.31 ml, 3.63 mmol) was added to a dimethoxyethanesolution (20 ml) of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (1.00 g, 3.30mmol) obtained in Example 5. After the temperature of the reactionmixture was elevated to room temperature, it was cooled again to −78° C.To the reaction mixture was added ethyl 6-bromohexanoate (706 μl, 3.96mmol), followed by stirring at room temperature for 18 hours. Thereaction mixture was added with water and then the mixture was extractedwith dichloromethane. The extracts were combined, washed with brine,dried over magnesium sulfate and then, concentrated, whereby an estercompound was obtained as a crude product. The resulting ester compoundwas dissolved in tetrahydrofuran (20 ml). To the resulting solution wasadded an aqueous solution (6 ml) of lithium hydroxide (96.0 mg, 4.00mmol). The mixture was stirred at room temperature for 18 hours. Afterthe reaction mixture was made acidic with 1N hydrochloric acid, the acidmixture was extracted with dichloromethane. The extracts were combined,washed with brine, dried over magnesium sulfate and then concentrated.The resulting solid was recrystallized from ethyl acetate-hexane,whereby the title compound (931 mg, 2.23 mmol, 68%) was obtained as acolorless solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.22-1.90 (7H, m), 2.30 (2H, t, J=7.3 Hz),2.40-2.48 (1H, m), 4.51 (1H, dd, J=11.7, 2.9 Hz), 6.83 (1H, td, J=9.0,4.4 Hz), 6.94-7.01 (1H, m), 7.22-7.26 (1H, m), 7.38 (2H, d, J=8.5 Hz),7.53 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3487, 2941, 2860, 1728, 1496, 1414, 1321, 1217, 1176,1149, 1086, 1014, 818, 787, 756, 633, 536, 478.

mp: 72-76° C.

MS m/z: 417 (M⁺+H).

Anal. calcd for C₁₉H₁₉ClF₂O₄S.0.5H₂O: C, 53.59; H, 4.73; Cl, 8.32; F,8.92; S, 7.53. Found: C, 53.83; H, 4.67; Cl, 8.39; F, 8.94; S, 7.72.

Example 2067-[(4-Chlorophenyl)sulfonyl]-7-(2,5-difluorophenyl)-1-(1-pyrrolidinyl)-1-heptanone

Under an argon atmosphere and at −15° C., N-methylmorpholine (53.9 μl,0.491 mmol) and isobutyl chloroformate (64.1 μl, 0.491 mmol) were addedto a tetrahydrofuran solution (5 ml) of7-[(4-chlorophenyl)sulfonyl]-7-(2,5-difluorophenyl)heptanoic acid (195mg, 0.468 mmol). The resulting mixture was stirred at −15° C. for 5minutes. Pyrrolidine (46.9 μl, 0.562 mmol) was added and the mixture wasstirred at room temperature for 1 hour. The reaction mixture was dilutedwith dichloromethane, washed successively with a saturated aqueoussolution of sodium bicarbonate, water and brine, dried over magnesiumsulfate and then concentrated. The residue thus obtained was subjectedto flash chromatography on a silica gel column, and the fractionobtained from the hexane:ethyl acetate=3:7 eluate was concentrated. Theresulting solid was recrystallized from ethyl acetate-hexane, wherebythe title compound (171 mg, 0.364 mmol, 78%) was obtained as a whitesolid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.21-1.43 (4H, m), 1.54-1.67 (2H, m),1.80-1.98 (4H, m), 2.03-2.15 (1H, m), 2.19 (2H, t, J=7.6 Hz), 2.38-2.46(1H, m), 3.36 (2H, t, J=6.8 Hz), 3.44 (2H, t, J=6.8 Hz), 4.51 (1H, dd,J=11.5, 2.9 Hz), 6.83 (1H, td, J=9.0, 4.4 Hz), 6.94-7.01 (1H, m), 7.23(1H, ddd, J=8.8, 5.4, 3.2 Hz), 7.38 (2H, d, J=8.8 Hz), 7.53 (2H, d,J=8.8 Hz).

IR (ATR) cm⁻¹: 2960, 1630, 1583, 1496, 1442, 1315, 1228, 1196, 1149,1086, 1011, 872, 841, 822, 787, 756, 633, 536, 467.

mp: 106-106° C.

MS m/z: 470 (M⁺+H).

Anal. calcd for C₂₃H₂₆ClF₇NO₃S: C, 58.78; H, 5.58; Cl, 7.54; F, 8.08; N,2.98; S, 6.82. Found: C, 58.53; H, 5.49; Cl, 7.66; F, 8.19; N, 3.06; S,8.82.

Example 2073-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)-1-propanol

Process 1: At 0° C., lithium aluminum hydride (a 1.0M tetrahydrofuransolution, 6.74 ml, 6.74 mmol) was added dropwise to a tetrahydrofuransolution (10 ml) of the ethyl3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propionate (1.31 g,3.37 mmol) obtained in Example 25. The mixture was then was stirred atroom temperature for 3 hours. After cooling the reaction mixture to 0°C., and addition of a saturated aqueous ammonium chloride solution, themixture was stirred at room temperature for 15 hours. The solid thusprecipitated was filtered off. The solution thus obtained was dilutedwith ether, washed with brine, dried over magnesium sulfate and then,concentrated. The residue thus obtained was recrystallized from ethylacetate-hexane, whereby the title compound (397 mg, 1.14 mmol, 34%) wasobtained as a colorless solid.

Process 2: Under an argon atmosphere and at −78° C., n-butyl lithium (a1.57M hexane solution, 4.62 ml, 7.26 mmol) was added to adimethoxyethane solution (50 ml) of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (2.00 g, 6.60mmol) obtained in Example 5. The temperature of the resulting mixturewas elevated to room temperature, and stirring was performed for 15minutes. After cooling the reaction mixture to −78° C., adimethoxyethane solution (5 ml) oft-butyl-(2-iodoethyloxy)dimethylsilane (2.08 g, 7.26 mmol) was addedthereto. The resulting mixture was stirred at room temperature for 15hours. Water was added to the reaction mixture, followed by extractionwith ether. The extracts were combined, washed successively with waterand brine, dried over magnesium sulfate and then, concentrated. Theresidue thus obtained was subjected to short silica gel chromatography(hexane:ethyl acetate=7:1) to remove high-polarity impurities. Theresulting oil was dissolved in tetrahydrofuran (50 ml), and to theresulting solution was added tetrabutylammonium fluoride (a 1Mtetrahydrofuran solution, 14.5 ml, 14.5 mmol). After stirring for 2days, the solvent was distilled off. The residue thus obtained wasdissolved in dichloromethane, followed by successive washing with 1Nhydrochloric acid, water, and brine, drying over magnesium sulfate andconcentration. The residue thus obtained was subjected to chromatographyon a silica gel column, and the fraction obtained from the hexane:ethylacetate=1:1 eluate was concentrated, whereby the title compound (2.07 g,5.82 mmol, 88%) was obtained as a colorless solid.

¹H-NMR (CDCl₃) δ 2.27 (1H, ddd, J=19.3, 10.3, 5.1 Hz), 2.72 (1H, ddd,J=19.3, 9.0, 3.9 Hz), 3.48 (1H, td, J=10.5, 4.4 Hz), 3.85 (1H, td,J=10.5, 5.1 Hz), 4.85 (1H, dd, J=10.3, 3.9 Hz), 6.84 (1H, td, J=9.0, 4.4Hz), 6.95-7.02 (1H, m), 7.23-7.27 (1H, m), 7.31 (2H, d, J=8.5 Hz), 7.55(2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3519, 3043, 2964, 2922, 2875, 1576, 1495, 1427, 1396,1308, 1186, 1147, 1084, 1036, 957, 895, 818, 786, 752, 708, 625, 521,467.

mp: 147-149° C.

MS m/z: 347 (M⁺+H).

Anal. calcd for C₁₅H₁₃ClF₂O₃S: C, 51.95; H, 3.78; Cl, 10.22; F, 10.96;S, 9.25. Found: C, 51.89; H, 3.75; Cl, 10.15; F, 10.90; S, 9.36.

Example 2083-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl=1-pyrrolidinecarboxylate

In dichloromethane (4 ml) was dissolved3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)-1-propanol (150 mg,0.432 mmol), followed by the addition of triethylamine (63.2 μl, 0.454mmol) and 4-nitrophenyl chloroformate (91.7 mg, 0.454 mmol). Theresulting mixture was stirred at room temperature for 20 hours.Pyrrolidine (43.2 μl, 0.518 mmol) and triethylamine (72.1 μl, 0.518mmol) were added and the mixture was stirred at room temperature for 18hours. The reaction mixture was concentrated. The residue thus obtainedwas subjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate=3:2 eluate wasconcentrated. The resulting colorless solid was recrystallized fromhexane, whereby the title compound (84.0 mg, 0.189 mmol, 44%) wasobtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.77-1.88 (4H, m), 2.37-2.47 (1H, m),2.75-3.84 (1H, m), 3.09-3.20 (2H, m), 3.28-3.34 (2H, m), 3.89 (1H, ddd,J=11.3, 8.3, 4.4 Hz), 4.22 (1H, dt, J=11.3, 5.6 Hz), 4.70 (1H, dd,J=11.3, 3.6 Hz), 6.83 (1H, td, J=9.1, 4.4 Hz), 6.95-7.02 (1H, m),7.20-7.26 (1H, m), 7.39 (2H, d, J=8.6 Hz), 7.54 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 2974, 2879, 1685, 1585, 1496, 1427, 1373, 1306, 1178,1149, 1091, 816, 766, 754, 710, 631, 553, 523, 467, 444.

mp: 109-110° C.

MS m/z: 444 (M⁺+H).

Anal. calcd for C₂₀H₂₀ClF₂NO₄S: C, 54.12; H, 4.54; Cl, 7.99; F, 8.56; N,3.16; S, 7.37. Found: C, 53.93; H, 4.49; Cl, 8.00; F, 8.50; N, 3.22; S,7.37.

Example 2093-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl=4-benzyl-1-piperazinecarboxylatehydrochloride

The 3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)-1-propanol (150mg, 0.432 mmol) obtained in Example 207 was dissolved in dichloromethane(4 ml), followed by the addition of triethylamine (63.2 μl, 0.454 mmol)and 4-nitrophenyl chloroformate (91.7 mg, 0.454 mmol). The resultingmixture was stirred at room temperature for 18 hours. To the reactionmixture were added N-benzylpiperazine (90.3 μl, 0.518 mmol) andtriethylamine (72.1 μl, 0.518 mmol) and the mixture was stirred at roomtemperature for 24 hours. The reaction mixture was then concentrated.The residue thus obtained was subjected to flash chromatography on asilica gel column, and the fraction obtained from the hexane:ethylacetate-1:1 eluate was concentrated. The resulting colorless solid wasdissolved in ethanol, followed by the addition of 1N hydrochloric acid(0.5 ml). The mixture was then concentrated to dryness. The resultingsolid was recrystallized from ethanol, whereby the title compound (132mg, 0.226 mmol, 52%) was obtained as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ: 2.35-2.45 (1H, br m), 2.56-2.72 (2H, br m),2.79-2.88 (1H, m), 3.28-3.40 (2H, m), 3.63-4.28 (8H, m), 4.60 (1H, dd,J=10.8, 3.9 Hz), 6.82 (1H, td, J=9.1, 4.4 Hz), 6.96-7.02 (1H, m),7.18-7.26 (1H, br m), 7.39 (2H, d, J=8.6 Hz), 7.45-7.53 (5H, m),7.58-7.64 (2H, br).

IR (ATR) cm⁻¹: 2958, 2708, 2675, 1701, 1583, 1495, 1423, 1321, 1255,1217, 1153, 1142, 1092, 951, 827, 752, 700, 627, 555, 525, 468.

mp: 184-189° C.

MS m/z: 549 (M⁺+H).

Anal. calcd for C₂₇H₂₇ClF₂N₂O₄S.HCl: C, 55.39; H, 4.82; Cl, 12.11; F,6.49; N, 4.78; S, 5.48. Found: C, 55.11; H, 4.80; Cl, 11.92; F, 6.36; N,4.85; S, 5.54.

Example 2103-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl=N-(2-hydroxyethyl)-N-methylcarbamate

In dichloromethane (4 ml) was dissolved the3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)-1-propanol (150 mg,0.432 mmol) obtained in Example 207, followed by the addition oftriethylamine (63.2 μl, 0.454 mmol) and 4-nitrophenyl chloroformate(91.7 mg, 0.454 mmol). The resulting mixture was stirred at roomtemperature for 20 hours. To the reaction mixture were addedN-methylethanolamine (41.6 μl, 0.518 mmol) and triethylamine (72.1 μl,0.518 mmol) and the resulting mixture was stirred at room temperaturefor 24 hours. The reaction mixture was then concentrated. The residuethus obtained was subjected to flash chromatography on a silica gelcolumn, and the fraction obtained from the hexane:ethyl acetate=1:2eluate was concentrated, whereby the title compound (136 mg, 0.304 mmol,70%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 2.33-2.48 (1H, br m), 2.77-2.97 (4H, m),3.27-3.43 (2H, br m), 3.68-3.78 (2H, br s), 3.87-3.98 (1H, br m),4.19-4.30 (1H, br m), 4.65-4.77 (1H, br m), 6.84 (1H, td, J=9.1, 4.4Hz), 6.95-7.02 (1H, m), 7.21-7.26 (1H, m), 7.39 (2H, d, J=8.8 Hz), 7.54(2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 3423, 2943, 1685, 1583, 1495, 1317, 1279, 1215, 1147,1080, 1012, 827, 754, 708, 627, 555, 467.

MS m/z: 448 (M⁺+H).

EI-MS: 447.0699 (Calcd for C₁₉H₂₀ClF₂NO₅S: 447.0719)

Example 2113-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl=4-morpholinecarboxylate

In dichloromethane (4 ml) was dissolved the3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)-1-propanol (150 mg,0.432 mmol) obtained in Example 207, followed by the addition oftriethylamine (63.2 μl, 0.454 mmol) and 4-nitrophenyl chloroformate(91.7 mg, 0.454 mmol). The resulting mixture was stirred at roomtemperature for 20 hours. To the reaction mixture were added morpholine(45.1 μl, 0.518 mmol) and triethylamine (72.1 μl, 0.518 mmol). Theresulting mixture was stirred at room temperature for 2 hours. Thereaction mixture was diluted with dichloromethane, washed successivelywith a saturated aqueous solution of sodium bicarbonate and brine, driedover magnesium sulfate and then, concentrated. The residue thus obtainedwas subjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate=3:2 eluate wasconcentrated. The solid thus obtained was recrystallized from ethylacetate-hexane, whereby the title compound (123 mg, 0.267 mmol, 62%) wasobtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 2.39-2.48 (1H, m), 2.79-2.88 (1H, m),3.19-3.47 (4H, br), 3.52-3.70 (4H, br s), 3.97 (1H, ddd, J=11.2, 8.3,5.1 Hz), 4.23 (1H, dt, J=11.2, 5.6 Hz), 4.65 (1H, dd, J=11.2, 3.4 Hz),6.84 (1H, td, J=9.0, 4.6 Hz), 6.97-7.03 (1H, m), 7.22-7.26 (1H, m), 7.40(2H, d, J=8.5 Hz), 7.53 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3086, 2864, 1684, 1576, 1498, 1469, 1427, 1311, 1281,1240, 1221, 1178, 1142, 1080, 837, 773, 752, 710, 633, 557, 528, 471.

mp: 140-141° C.

MS m/z: 460 (M⁺+H).

Anal. calcd for C₂₀H₂₀ClF₂NO₅S: C, 52.23; H, 4.38; Cl, 7.71; F, 8.26; N,3.05; S, 6.97. Found: C, 51.95; H, 4.29; Cl, 7.80; F, 8.32; N, 3.12; S,7.12.

Example 2123-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl=4-phenyl1-piperazinecarboxylate

The 3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)-1-propanol (150mg, 0.432 mmol) obtained in Example 207 was dissolved in dichloromethane(6 ml), followed by the addition of triethylamine (63.2 μl, 0.454 mmol)and 4-nitrophenyl chloroformate (91.7 mg, 0.454 mmol). The resultingmixture was stirred at room temperature for 18 hours. AfterN-phenylpiperazine (79.1 μl, 0.518 mmol) and triethylamine (72.1 μl,0.518 mmol) were added, the mixture was stirred at room temperature for4 hours. The reaction mixture was diluted with dichloromethane, washedsuccessively with a saturated aqueous solution of sodium bicarbonate andbrine, dried over magnesium sulfate and then, concentrated. The residuethus obtained was subjected to flash chromatography on a silica gelcolumn, and the fraction obtained from the hexane:ethyl acetate=4:1eluate was concentrated. The solid thus obtained was recrystallized fromethyl acetate-hexane, whereby the title compound (158 mg, 0.295 mmol,68%) was obtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 2.40-2.50 (1H, m), 2.80-2.89 (1H, m),3.00-3.15 (4H, br s), 3.37-3.65 (4H, m), 3.98 (1H, ddd, J=11.2, 8.3, 5.1Hz), 4.24 (1H, dt, J=11.2, 5.6 Hz), 4.67 (1H, dd, J=11.2, 3.9 Hz), 6.84(1H, td, J=9.0, 4.6 Hz), 6.89-6.93 (3H, m), 6.95-7.03 (1H, m), 7.23-7.32(3H, m), 7.39 (2H, d, J=8.3 Hz), 7.54 (2H, d, J=8.3 Hz).

IR (ATR) cm⁻¹: 2829, 1687, 1599, 1581, 1495, 1437, 1321, 1223, 1151,1130, 1084, 1001, 930, 814, 758, 692, 634, 552, 469.

mp: 127-129° C.

MS m/z: 535 (M⁺+H).

Anal. calcd for C₂₆H₂₅ClF₂N₂O₄S: C, 58.37; H, 4.71; Cl, 6.63; F, 7.10;N, 5.24; S, 5.99. Found: C, 58.28; H, 4.86; Cl, 6.56; F, 7.17; N, 5.30;S, 6.13.

Example 2133-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl=4-methyl-1-piperazinecarboxylatehydrochloride

The 3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)-1-propanol (150mg, 0.432 mmol) obtained in Example 207 was dissolved in dichloromethane(4 ml), followed by the addition of triethylamine (63.2 μl, 0.454 mmol)and 4-nitrophenyl chloroformate (91.7 mg, 0.454 mmol). The resultingmixture was stirred at room temperature for 18 hours. After addition ofN-methylpiperazine (57.4 μl, 0.518 mmol) and triethylamine (72.1 μl,0.518 mmol), the mixture was stirred at room temperature for 24 hours.The reaction mixture was diluted with dichloromethane, washedsuccessively with a saturated aqueous solution of sodium bicarbonate andbrine, dried over sodium sulfate and then, concentrated. The residuethus obtained was subjected to flash chromatography on a silica gelcolumn, and the fraction obtained from the dichloromethane:methanol=30:1eluate was concentrated. The solid thus obtained was dissolved inethanol. After addition of 1N hydrochloric acid-ethanol (2 ml), theresulting mixture was concentrated to dryness. The solid thus obtainedwas washed with ethyl acetate, whereby the title compound (96.9 mg,0.189 mmol, 44%) was obtained as a pale yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 2.37-2.47 (1H, m), 2.60-2.92 (8H, m),3.20-4.30 (6H, m), 4.62 (1H, dd, J=10.0, 3.4 Hz), 6.85 (1H, td, J=9.0,4.4 Hz), 6.98-7.05 (1H, m), 7.19-7.28 (1H, m), 7.39 (2H, d, J=8.8 Hz),7.51 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 2387, 1699, 1583, 1496, 1473, 1425, 1317, 1255, 1232,1176, 1149, 1084, 978, 829, 758, 710, 629, 555, 467.

MS m/z: 473 (M⁺+H).

Anal. calcd for C₂₂H₂₃ClF₂N₂O₄S.HCl.0.25H₂O: C, 49.08; H, 4.81; Cl,13.80; F, 7.39; N, 5.45; S, 6.24. Found: C, 49.03; H, 5.01; Cl, 13.31;F, 7.31; N, 5.54; S, 6.28.

Example 2143-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl=carbamate

The 3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)-1-propanol (200mg, 0.576 mmol) obtained in Example 207 was dissolved in dichloromethane(4 ml), followed by the addition of triethylamine (84.2 μl, 0.605 mmol)and 4-nitrophenyl chloroformate (122 mg, 0.605 mmol). The resultingmixture was stirred at room temperature for 18 hours. Concentratedaqueous ammonia (2.5 ml) was added and the mixture was vigorouslystirred at room temperature for 3 hours. After separation of the waterlayer, the organic layer was washed with water and brine, dried oversodium sulfate and then, concentrated. The residue thus obtained wassubjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate=1:1 eluate wasconcentrated. The solid thus obtained was recrystallized from ethylacetate-hexane, whereby the title compound (156 mg, 0.353 mmol, 61%) wasobtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 2.34-2.44 (1H, m), 2.77-2.86 (1H, m), 3.89(1H, ddd, J=11.0, 9.0, 5.1 Hz), 4.19 (1H, dt, J=11.0, 5.6 Hz), 4.53 (2H,br s), 4.69 (1H, dd, J=11.0, 3.9 Hz), 6.84 (1H, td, J=9.0, 4.4 Hz),6.97-7.03 (1H, m), 7.24 (1H, ddd, J=8.8, 5.4, 3.2 Hz), 7.40 (2H, d,J=8.5 Hz), 7.54 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3452, 3263, 1734, 1606, 1493, 1396, 1313, 1230, 1144,1080, 1051, 957, 829, 795, 752, 623, 553, 465.

mp: 139-140° C.

MS m/z: 390 (M⁺+H).

Anal. calcd for C₁₆H₁₄ClF₂NO₄S: C, 49.30; H, 3.62; Cl, 9.10; F, 9.75; N,3.59; S, 8.23. Found: C, 49.13; H, 3.53; Cl, 9.19; F, 9.86; N, 3.68; S,8.35.

Example 215 3-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propylN-methylcarbamate

The 3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)-1-propanol (200mg, 0.576 mmol) obtained in Example 207 was dissolved in dichloromethane(4 ml), followed by the addition of triethylamine (84.2 μl, 0.605 mmol)and 4-nitrophenyl chloroformate (122 mg, 0.605 mmol). The resultingmixture was stirred at room temperature for 15 hours. After addition ofmethylamine (a 2.00M tetrahydrofuran solution, 2.0 ml, 4.00 mmol), themixture was stirred at room temperature for 24 hours. Methylamine (a2.00M tetrahydrofuran solution, 3.0 ml, 4.00 mmol) was added and themixture was stirred at room temperature for 5 hours. The reactionmixture was diluted with dichloromethane, washed successively with asaturated aqueous solution of sodium bicarbonate, water and brine, driedover magnesium sulfate and then, concentrated. The residue thus obtainedwas subjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate=3:2 eluate wasconcentrated. The concentrate was purified further by high performanceliquid chromatography (using a mixed solvent ofwater/acetonitrile/formic acid) to yield the title compound (62.1 mg,0.154 mmol, 27%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 2.32-2.45 (1H, m), 2.60-2.85 (4H, m),3.83-3.90 (1H, m), 4.19 (1H, dt, J=11.0, 5.4 Hz), 4.49 (1H, br s), 4.68(1H, m), 6.84 (1H, td, J=9.0, 4.4 Hz), 6.96-7.02 (1H, m), 7.20-7.26 (1H,m), 7.39 (2H, d, J=8.5 Hz), 7.54 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3403, 1709, 1527, 1496, 1477, 1317, 1248, 1147, 1086,1012, 827, 754, 629, 555, 467.

MS m/z: 404 (M⁺+H).

FAB-MS: 404.0551 (calcd for C₁₇H₁₇ClF₂NO₄S: 404.0535)

Example 2163-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl=N,N-dimethylcarbamate

The 3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)-1-propanol (200mg, 0.576 mmol) obtained in Example 207 was dissolved in dichloromethane(4 ml), followed by the addition of triethylamine (84.2 μl, 0.605 mmol)and 4-nitrophenyl chloroformate (122 mg, 0.605 mmol). The resultingmixture was stirred at room temperature for 6 hours. To the reactionmixture was added a 50% aqueous dimethylamine solution (2 ml). Themixture was stirred at room temperature for 15 hours. After furtheraddition of a 50% aqueous dimethylamine solution (1 ml), stirring wasconducted at room temperature for 1 hour. The reaction mixture wasdiluted with dichloromethane, washed with 1N potassium hydroxide, waterand brine, dried over magnesium sulfate and then, concentrated. Theresidue thus obtained was subjected to flash chromatography on a silicagel column, and the fraction obtained from the hexane:ethyl acetate=3:2eluate was concentrated, whereby the title compound (151 mg, 0.362 mmol,63%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 2.38-2.46 (1H, m), 2.70-2.88 (7H, m), 3.89(1H, ddd, J=11.2, 8.3, 4.9 Hz), 4.21 (1H, dt, J=11.2, 5.6 Hz), 4.69 (1H,dd, J=11.2, 3.9 Hz), 6.83 (1H, td, J=9.0, 4.4 Hz), 6.95-7.02 (1H, m),7.23 (1H, ddd, J=8.8, 5.4, 3.4 Hz), 7.39 (2H, d, J=8.5 Hz), 7.54 (2H, d,J=8.5 Hz).

IR (ATR) cm⁻¹: 2943, 1697, 1583, 1495, 1402, 1319, 1279, 1223, 1180,1147, 1082, 1012, 829, 754, 710, 623, 555, 525, 467.

MS m/z: 418 (M⁺+H).

FAB-MS: 418.0692 (calcd for C₁₈H₁₉ClF₂NO₄S: 418.0691)

Example 2172-[1-[(4-Chlorophenyl)sulfonyl]-2-phenylethyl]-1,4-difluorobenzene

Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.60 Mhexane solution, 459 μl, 0.734 mmol) was added to a dimethoxyethanesolution (50 ml) of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (202 mg, 0.667mmol) obtained in Example 5. The temperature of the resulting mixturewas then elevated to room temperature. After the reaction mixture wascooled to −78° C., benzylbromide (87.2 μl, 0.734 mmol) was addeddropwise thereto. While elevating the temperature of the reactionmixture to room temperature, stirring was conducted for 15 hours. Waterwas added to the reaction mixture, followed by extraction with ethylacetate. The extracts were combined, washed with brine, dried overmagnesium sulfate and then, concentrated. The residue thus obtained wassubjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate-6:1 eluate wasconcentrated. The solid thus obtained was recrystallized from ethylacetate-hexane, whereby the title compound (125 mg, 0.318 mmol, 48%) wasobtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 3.32 (1H, dd, J=13.9, 11.7 Hz), 3.84 (1H, dd,J=13.9, 3.4 Hz), 4.81 (1H, dd, J=11.7, 3.4 Hz), 6.69 (1H, td, J=9.3, 4.4Hz), 6.87-6.94 (1H, m), 7.00-7.05 (2H, m), 7.12-7.20 (3H, m), 7.38-7.43(3H, m), 7.57 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 1574, 1493, 1303, 1279, 1219, 1144, 1083, 1011, 879, 825,785, 742, 698, 633, 555, 526, 467.

mp: 160-161° C.

MS m/z: 393 (M⁺+H).

Anal. calcd for C₂₀H₁₅ClF₂NO₂S: C, 61.15; H, 3.85; Cl, 9.02; F, 9.67; S,8.16. Found: C, 61.07; H, 3.87; Cl, 8.95; F, 9.95; S, 8.30.

Example 2182-[2-[(4-Chlorophenyl)sulfonyl]-2-(2,5-difluorophenyl)ethyl]pyridine

Under an argon atmosphere, the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (150 mg, 0.495mmol) obtained in Example 5 and 2-pyridylmethanol (95.5 μl, 0.990 mmol)were dissolved in toluene (5 ml), followed by the addition ofcyanomethylenetri-n-butylphosphorane (239 mg, 0.990 mmol). The resultingmixture was heated under reflux for 18 hours under an argon atmosphere.The reaction mixture was then concentrated. The residue thus obtainedwas subjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate=1:1 eluate wasconcentrated. The solid thus obtained was recrystallized from ethylacetate-hexane, whereby the title compound (96.6 mg, 0.245 mmol, 49%)was obtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 3.49 (1H, dd, J=14.7, 10.7 Hz), 3.95 (1H, dd,J=14.7, 4.6 Hz), 5.37 (1H, dd, J=11.0, 4.2 Hz), 6.73 (1H, td, J=9.0, 4.4Hz), 6.86-6.94 (1H, m), 7.03-7.07 (2H, m), 7.33 (1H, ddd, J=8.8, 5.4,3.2 Hz), 7.39 (2H, d, J=8.5 Hz), 7.49 (1H, td, J=7.8, 1.7 Hz), 7.60 (2H,d, J=8.5 Hz), 8.41 (1H, d, J=4.4 Hz).

IR (ATR) cm⁻¹: 3041, 1585, 1496, 1433, 1321, 1277, 1149, 1086, 910, 825,779, 746, 644, 536, 461, 436.

mp: 105-107° C.

MS m/z: 394 (M⁺+H).

Anal. calcd for C₁₉H₁₄ClF₂NO₂S: C, 57.94; H, 3.58; Cl, 9.00; F, 9.65; N,3.56; S, 8.14. Found: C, 57.85; H, 3.59; Cl, 8.97; F, 9.52; N, 3.69; S,8.28.

Example 2193-[2-[(4-Chlorophenyl)sulfonyl]-2-(2,5-difluorophenyl)ethyl]pyridine

Under an argon atmosphere, the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (120 mg, 0.396mmol) obtained in Example 5 and 3-pyridylmethanol (50.1 μl, 0.515 mmol)were dissolved in toluene (4 ml), followed by the addition ofcyanomethylenetri-n-butylphosphorane (124 mg, 0.515 mmol). The resultingmixture was heated under reflux for 18 hours under an argon atmosphere.The reaction mixture was then concentrated. The residue thus obtainedwas subjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate=3:7 eluate wasconcentrated. The solid thus obtained was recrystallized from ethylacetate-hexane, whereby the title compound (90.3 mg, 0.229 mmol, 58%)was obtained as colorless columnar crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 3.35 (1H, dd, J=14.4, 11.7 Hz), 3.85 (1H, dd,J=14.4, 3.9 Hz), 4.77 (1H, dd, J=11.7, 3.2 Hz), 6.71 (1H, td, J=9.0, 4.4Hz), 6.90-6.97 (1H, m), 7.13 (1H, dd, J=8.1, 4.9 Hz), 7.37-7.45 (4H, m),7.57 (2H, d, J=8.8 Hz), 8.30 (1H, d, J=2.0 Hz), 8.41 (1H, dd, J=4.9, 1.5Hz).

IR (ATR) cm⁻¹: 3078, 1577, 1495, 1427, 1313, 1279, 1217, 1144, 1082,1012, 823, 775, 752, 706, 646, 557, 532, 464.

mp: 162-163° C.

MS m/z: 394 (M⁺+H).

Anal. calcd for C₁₉H₁₄ClF₂NO₂S: C, 57.94; H, 3.58; Cl, 9.00; F, 9.65; N,3.56; S, 8.14. Found: C, 57.80; H, 3.51; Cl, 9.06; F, 9.53; N, 3.71; S,8.22.

Example 2204-[2-[(4-Chlorophenyl)sulfonyl]-2-(2,5-difluorophenyl)ethyl]pyridine

Under an argon atmosphere, the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.660mmol) obtained in Example 5 and 4-pyridylmethanol (144 mg, 1.32 mmol)were dissolved in toluene (6 ml), followed by the addition ofcyanomethylenetri-n-butylphosphorane (318 mg, 1.32 mmol). The resultingmixture was heated under reflux for 15 hours under an argon atmosphere.The reaction mixture was then concentrated. The residue thus obtainedwas subjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate=1:2 eluate wasconcentrated. The solid thus obtained was recrystallized from ethylacetate, whereby the title compound (81.4 mg, 0.207 mmol, 31%) wasobtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 3.34 (1H, dd, J=14.2, 12.0 Hz), 3.84 (1H, dd,J=14.2, 3.4 Hz), 4.81 (1H, dd, J=12.0, 3.4 Hz), 6.72 (1H, td, J=9.0, 4.6Hz), 6.91-6.96 (1H, m), 6.97 (2H, d, J=6.1 Hz), 7.34-7.39 (1H, m), 7.40(2H, d, J=8.5 Hz), 7.56 (2H, d, J=8.5 Hz), 8.42 (2H, dd, J=4.4, 1.5 Hz).

IR (ATR) cm⁻¹: 1597, 1493, 1417, 1301, 1277, 1219, 1174, 1144, 1082,1012, 985, 883, 850, 808, 754, 706, 631, 606, 557, 524, 469.

mp: 129° C.

MS m/z: 394 (M⁺+H).

Anal. calcd for C₁₉H₁₄ClF₂NO₂S: C, 57.94; H, 3.58; Cl, 9.00; F, 9.65; N,3.56; S, 8.14. Found: C, 57.67; H, 3.45; Cl, 9.00; F, 9.78; N, 3.64; S,8.31.

Example 2212-[3-(4-Chlorophenylsulfonyl)-3-(2,5-difluorophenyl)propyl]thiophene

Under an argon atmosphere, the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330mmol) obtained in Example 5 and 2-(2-thienyl)ethanol (144 mg, 1.32 mmol)were dissolved in toluene (3 ml), followed by the addition ofcyanomethylenetri-n-butylphosphorane (159 mg, 0.660 mmol). The resultingmixture was heated under reflux for 15 hours under a nitrogenatmosphere. The reaction mixture was then concentrated. The residue thusobtained was subjected to flash chromatography on a silica gel column,and the fraction obtained from the hexane:ethyl acetate=12:1 eluate wasconcentrated, whereby the title compound (90.0 mg, 0.218 mmol, 53%) wasobtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 2.42-2.52 (1H, m), 2.68-2.83 (2H, m),2.85-2.92 (1H, m), 4.54 (1H, dd, J=11.2, 2.4 Hz), 6.70 (1H, d, J=2.7Hz), 6.86 (1H, td, J=9.0, 4.4 Hz), 6.90 (1H, dd, J=5.1, 3.4 Hz),6.97-7.05 (1H, m), 7.14 (1H, dd, J=5.1, 1.2 Hz), 7.24-7.29 (1H, m), 7.38(2H, d, J=8.5 Hz), 7.51 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3086, 1583, 1495, 1425, 1394, 1317, 1277, 1147, 1084,1012, 827, 754, 694, 627, 555, 465.

MS m/z: 413 (M⁺+H).

FAB-MS: 413.0251 (Calcd for C₁₉H₁₆ClF₂O₂S: 413.0248).

Example 222 EthylN-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]carbamate

Under a nitrogen atmosphere and at 0° C., triethylamine (81.5 μl, 0.586mmol) and diphenylphosphoric azide (126 μl, 0.586 mmol) were added to atoluene solution (5 ml) of the4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyric acid (200 mg,0.533 mmol) obtained in Example 200, followed by stirring at 0° C. for 2hours. The reaction mixture was heated under reflux for 3 hours. Aftercooling to room temperature and addition of ethanol (2 ml), the mixturewas heated under reflux for further 2 hours. The reaction mixture wasthen concentrated. The residue thus obtained was dissolved indichloromethane. The resulting solution was washed successively with asaturated aqueous solution of potassium bicarbonate, water and brine,dried over magnesium sulfate and then, concentrated. The residue thusobtained was subjected to flash chromatography on a silica gel column,and the fraction obtained from the hexane:ethyl acetate=1:3 eluate wasconcentrated. The solid thus obtained was recrystallized from ethylacetate-hexane, whereby the title compound (129 mg, 0.309 mmol, 58%) wasobtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.21 (3H, t, J=7.1 Hz), 2.24-2.36 (1H, m),2.60-2.70 (1H, m), 3.10-3.33 (2H, m), 4.06 (2H, q, J=7.1 Hz), 4.60 (1H,dd, J=11.0, 4.6 Hz), 4.70 (1H, br s), 6.83 (1H, td, J=9.0, 4.4 Hz),6.95-7.02 (1H, m), 7.21-7.26 (1H, m), 7.38 (2H, d, J=8.3 Hz), 7.52 (2H,d, J=8.3 Hz). IR (ATR) cm⁻¹: 3394, 1691, 1576, 1525, 1496, 1396, 1304,1281, 1250, 1225, 1149, 1086, 1028, 1012, 974, 885, 829, 791, 766, 752,629, 553, 465.

mp: 121-122° C.

MS m/z: 418 (M⁺+H).

Anal. calcd for C₁₈H₁₈ClF₂NO₄S: C, 51.74; H, 4.34; Cl, 8.48; F, 9.09; N,3.35; S, 7.67. Found: C, 51.49; H, 4.43; Cl, 8.55; F, 9.13; N, 3.61; S,7.75.

Example 223 EthylN-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]-N-methylcarbamate

In tetrahydrofuran (4 ml) was dissolved ethylN-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]carbamate(100 mg, 0.239 mmol), followed by the addition of sodium hydride (60%dispersion in mineral oil, 11.5 mg, 0.287 mmol). The resulting mixturewas stirred at room temperature for 3 hours. Iodomethane (17.8 μl, 0.287mmol) was added and the mixture was stirred at room temperature for 15hours. Sodium hydride (60% dispersion in mineral oil, 5.00 mg, 0.125mmol) and iodomethane (10.0 μl, 0.161 mmol) were added, followed bystirring at room temperature for 24 hours. Water (5 ml) was added, andthe mixture was concentrated. The residue thus obtained was extractedwith ethyl acetate. The extract was washed with brine, dried overmagnesium sulfate and then concentrated. The residue thus obtained wassubjected to flash chromatography on a silica gel column, and thefraction obtained from the hexane:ethyl acetate=3:1 eluate wasconcentrated, whereby the title compound (83.2 mg, 0.193 mmol, 81%) wasobtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.11-1.27 (3H, br m), 2.20-2.35 (1H, br m),2.68-2.90 (4H, m), 3.18-3.35 (2H, m), 3.93-4.12 (2H, br m), 4.51 (1H, brs), 6.82 (1H, td, J=9.0, 4.6 Hz), 6.96-7.04 (1H, br m), 7.21-7.27 (1H,br m), 7.38 (2H, d, J=8.5 Hz), 7.51 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 2983, 1693, 1583, 1495, 1319, 1182, 1147, 1084, 1012,883, 827, 754, 710, 629, 555, 467.

MS m/z: 432 (M⁺+H).

FAB-MS: 432.0838 (calcd for C₁₉H₂₁ClF₂NO₄S: 432.0848)

Example 224 2-IodoethylN-[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyl]carbamate

Under a nitrogen atmosphere and at 0° C., triethylamine (157 μl, 1.13mmol) and diphenylphosphoric azide (243 μl, 1.13 mmol) were added to atoluene solution (5 ml) of the5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)valeric acid (400 mg,1.03 mmol) obtained in Example 202. The resulting mixture was stirred atroom temperature for 2 hours. The reaction mixture was heated underreflux for 3 hours. After cooling to room temperature and addition of2-iodoethanol (160 μl, 2.06 mmol), the mixture was heated under refluxfor further 1.5 hours. The reaction mixture diluted with ethyl acetatewas then washed successively with a saturated aqueous solution of sodiumbicarbonate, water, and brine, dried over magnesium sulfate and then,concentrated. The residue thus obtained was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate=3:1 eluate was concentrated. The solid thusobtained was recrystallized from ethyl acetate-hexane, whereby the titlecompound (300 mg, 0.538 mmol, 52%) was obtained as colorless needlecrystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.44-1.60 (2H, m), 2.05-2.17 (1H, in),2.44-2.55 (1H, m), 3.19 (2H, q, J=6.4 Hz), 3.28 (2H, t, J=6.8 Hz), 4.29(2H, t, J=6.8 Hz), 4.57 (1H, br m), 4.76 (1H, br s), 6.84 (1H, td,J=9.0, 4.4 Hz), 6.95-7.02 (1H, m), 7.23-7.28 (1H, m), 7.39 (2H, d, J=8.5Hz), 7.53 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3406, 1722, 1585, 1516, 1493, 1306, 1238, 1147, 1009,872, 822, 781, 752, 708, 627, 546, 525, 463.

mp: 100-101° C.

MS m/z: 558 (M⁺+H).

Anal. calcd for C₁₉H₁₉ClF₂₁NO₄S: C, 40.91; H, 3.43; Cl, 6.36; F, 6.81;N, 2.51; S, 5.75. Found: C, 40.79; H, 3.40; Cl, 6.41; F, 6.96; N, 2.61;S, 5.85.

Example 2253-[4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyl]-2-oxazolidinone

Under a nitrogen atmosphere and at 0° C., sodium hydride (60% dispersionin mineral oil, 13.6 mg, 0.340 mmol) was added to a tetrahydrofuransolution (5 ml) of 2-iodoethylN-[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyl]carbamate(158 mg, 0.283 mmol). The resulting mixture was stirred at roomtemperature for 18 hours. Water was added to the reaction mixture,followed by extraction with ethyl acetate. The extract was washed withbrine, dried over magnesium sulfate and then concentrated. The residuethus obtained was subjected to flash chromatography on a silica gelcolumn, and the fraction obtained from the hexane:ethyl acetate=1:2eluate was concentrated. The solid thus obtained was recrystallized fromethyl acetate-hexane, whereby the title compound (52.1 mg, 0.121 mmol,43%) was obtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.52-1.63 (2H, m), 2.05-2.16 (1H, m),2.42-2.51 (1H, m), 3.18-3.35 (2H, m), 3.50 (2H, t, J=8.3 Hz), 4.31 (2H,dd, J=8.8, 7.1 Hz), 4.60 (1H, dd, J=10.3, 4.9 Hz), 6.85 (1H, td, J=9.0,4.4 Hz), 6.96-7.02 (1H, m), 7.22-7.28 (1H, m), 7.39 (2H, d, J=8.5 Hz),7.54 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 2918, 1734, 1583, 1487, 1425, 1308, 1265, 1182, 1130,1086, 1012, 895, 804, 758, 708, 594, 577, 538, 478, 444.

mp: 156-159° C.

MS m/z: 430 (M⁺+H).

Anal. calcd for C₁₉H₁₈ClF₂NO₄S: C, 53.09; H, 4.22; Cl, 8.25; F, 8.84; N,3.26; S, 7.46. Found: C, 52.84; H, 4.15; Cl, 8.40; F, 8.96; N, 3.33; S,7.58.

Example 226 t-ButylN-[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyl]carbamate

Under a nitrogen atmosphere, triethylamine (126 μl, 0.907 mmol) anddiphenylphosphoric azide (195 μl, 0.907 mmol) were added to a toluenesolution (6 ml) of the5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)valeric acid (294 mg,0.533 mmol) obtained in Example 202. The resulting mixture was stirredat room temperature for 3 hours. The reaction mixture was heated underreflux for 3 hours. After cooling to room temperature and addition of2-methyl-2-propanol (1 ml), the mixture was stirred at 80° C. forfurther 18 hours. The reaction mixture was then concentrated and theresidue thus obtained was dissolved in dichloromethane. The resultingsolution was washed successively with a saturated aqueous solution ofpotassium bicarbonate, water and brine, dried over magnesium sulfate andthen, concentrated. The residue thus obtained was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate=4:1 eluate was concentrated to yield the titlecompound (171 mg, 0.383 mmol, 51%) as a white solid. The solid thusobtained was recrystallized from ethyl acetate-hexane, whereby colorlessneedle crystals were obtained.

¹H-NMR (400 MHz, CDCl₃) δ: 1.40-1.49 (11H, s), 2.05-2.14 (1H, m),2.43-2.52 (1H, m), 3.07-3.17 (2H, m), 4.48-4.60 (2H, m), 6.83 (1H, td,J=9.0, 4.4 Hz), 6.94-7.01 (1H, m), 7.24 (1H, ddd, J=8.8, 5.4, 3.2 Hz),7.38 (2H, d, J=8.5 Hz), 7.53 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3392, 2960, 1695, 1583, 1514, 1493, 1365, 1313, 1248,1174, 1147, 1084, 999, 827, 752, 644, 548, 528, 451.

mp: 119-120° C.

MS m/z: 460 (M⁺+H).

Anal. calcd for C₂₁H₂₄ClF₂NO₄S: C, 54.84; H, 5.26; Cl, 7.71; F, 8.26; N,3.05; S, 6.97. Found: C, 54.84; H, 5.31; Cl, 7.06; F, 8.36; N, 3.16; S,7.14.

Example 2274-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butylaminehydrochloride

Concentrated hydrochloric acid (2 ml) was added to an ethanol solution(2 ml) of t-butylN-[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyl]carbamate(104 mg, 0.226 mmol), followed by stirring at room temperature for 2hours. The reaction mixture was then concentrated. The residue thusobtained was recrystallized from ethanol-ethyl acetate, whereby thetitle compound (78.9 mg, 0.199 mmol, 88%) was obtained as colorlessneedle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.51-1.60 (1H, m), 1.63-1.75 (1H, m),2.18-2.28 (1H, m), 2.45-2.54 (1H, m), 2.95 (2H, ddd, J=8.5, 6.8, 3.2Hz), 4.76 (1H, dd, J=11.0, 4.6 Hz), 6.98 (1H, td, J=9.3, 4.4 Hz),7.09-7.17 (1H, m), 7.32 (1H, ddd, J=9.0, 5.6, 3.4 Hz), 7.52 (2H, d,J=8.8 Hz), 7.60 (2H, d, J=8.8 Hz). IR (ATR) cm⁻¹: 2951, 2871, 1583,1496, 1427, 1396, 1311, 1279, 1219, 1147, 1081, 1011, 870, 825, 742,706, 629, 536, 463.

mp: 232-233° C.

MS m/z: 360 (M⁺+H).

Anal. calcd for C₁₆H₁₆ClF₂NO₂S.HCl: C, 48.49; H, 4.32; Cl, 17.89; F,9.59; N, 3.53; S, 8.09. Found: C, 48.20; H, 4.27; Cl, 17.84; F, 9.61; N,3.63; S, 8.15.

Example 228N-[4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyl]nicotinamidehydrochloride

Under a nitrogen atmosphere and 0° C., N-methylmorpholine (44.6 μl,0.406 mmol) and nicotinic acid chloride hydrochloride (36.1 mg, 0.203mmol) were added to a dichloromethane solution (4 ml) of4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butylaminehydrochloride (67.0 mg, 0.169 mmol). After stirring at room temperaturefor 3 hours, the reaction mixture was diluted with dichloromethane,washed successively with a saturated aqueous solution of ammoniumchloride, water and brine, dried over magnesium sulfate and then,concentrated. The residue thus obtained was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate=1:3 eluate was concentrated. The resultingsolid was dissolved in ethanol. To the resulting solution was added 1Nhydrochloric acid-ethanol (0.5 ml), followed by concentration. The solidthus obtained was recrystallized from ethanol-ethyl acetate, whereby thetitle compound (67.1 mg, 0.134 mmol, 79%) was obtained as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 1.58-1.67 (2H, m), 2.18-2.28 (1H, m),2.42-2.52 (1H, m), 3.40 (1H, dt, J=13.7, 6.6 Hz), 3.51 (1H, dt, J=13.7,6.8 Hz), 4.81 (1H, m), 6.98 (1H, td, J=9.3, 4.4 Hz), 7.08-7.15 (1H, m),7.30 (1H, ddd, J=9.0, 5.6, 3.4 Hz), 7.50 (2H, d, J=8.8 Hz), 7.62 (2H, d,J=8.8 Hz), 8.18 (1H, dd, J=8.1, 5.9 Hz), 8.92 (1H, dd, J=8.1, 1.5 Hz),8.99 (1H, d, J=5.9 Hz), 9.22 (1H, d, J=1.2 Hz).

IR (ATR) cm⁻¹: 3282, 2457, 2096, 1977, 1666, 1547, 1493, 1302, 1234,1173, 1147, 1092, 1016, 883, 829, 760, 733, 673, 623, 528.

mp: 154-157° C.

MS m/z: 465 (M⁺+H).

Anal. calcd for C₂₂H₁₉ClF₂N₂O₃S.HCl: C, 52.70; H, 4.02; Cl, 14.14; F,7.58; N, 5.59; S, 6.40. Found: C, 52.59; H, 4.01; Cl, 14.19; F, 7.72; N,5.73; S, 6.56.

Example 2291-[4-(4-Chlorophenylsulfonyl)-4-(2,5-difluorophenyl)butyl]-2-pyrrolidinone

To a dichloromethane solution (6 ml) of the4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butylaminehydrochloride (120 mg, 0.303 mmol) obtained in Example 227 were addedN-methylmorpholine (250 μl, 2.69 mmol) and 4-chlorobutyric acid chloride(40.7 μl, 0.364 mmol). After stirring at room temperature for 1 hour,the reaction mixture was diluted with dichloromethane, washedsuccessively with a saturated aqueous solution of ammonium chloride,water and brine, dried over magnesium sulfate and then, concentrated.The residue thus obtained was dissolved in tetrahydrofuran (5 ml),followed by the addition of sodium hydride (60% dispersion in mineraloil, 14.2 mg, 0.356 mmol) and N,N-dimethylformamide (2 drops). Theresulting mixture was stirred at room temperature for 24 hours. Waterwas added and the resulting mixture was extracted with ethyl acetate.The extracts were combined, washed with brine, dried over magnesiumsulfate and then concentrated. The residue thus obtained was subjectedto flash chromatography on a silica gel column, and the fractionobtained from the hexane:ethyl acetate=1:1 eluate was concentrated,whereby the title compound (105 mg, 0.245 mmol, 82%) was obtained as acolorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.43-1.65 (2H, m), 1.97-2.12 (3H, m),2.32-2.43 (3H, m), 3.16 (1H, dt, J=13.7, 6.8 Hz), 3.28-3.42 (3H, m),4.67 (1H, dd, J=10.9, 3.4 Hz), 6.84 (1H, td, J=9.0, 4.4 Hz), 6.95-7.02(1H, m), 7.22-7.28 (1H, m), 7.39 (2H, d, J=8.5 Hz), 7.56 (2H, d, J=8.5Hz).

IR (ATR) cm⁻¹: 2941, 1676, 1583, 1495, 1425, 1394, 1319, 1279, 1147,1084, 1012, 827, 754, 707, 625, 555, 467.

MS m/z: 428 (M⁺+H).

FAB-MS: 428.0885 (Calcd for C₂₀H₂₁ClF₂NO₃S: 428.0899).

Example 230N-[4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyl]methanesulfonamide

Under a nitrogen atmosphere, N-methylmorpholine (51.0 μl, 0.465 mmol)and methanesulfonyl chloride (18.8 μl, 0.242 mmol) were added to adichloromethane solution (4 ml) of the4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butylaminehydrochloride (80.0 mg, 0.202 mmol) obtained in Example 227. Afterstirring at room temperature for 15 hours, N-methylmorpholine (156 μl,1.42 mmol) and methanesulfonyl chloride (10.0 μl, 0.129 mmol) wereadded. The resulting mixture was stirred at room temperature for 2hours. After dilution with dichloromethane, the mixture was successivelywashed with a saturated aqueous solution of ammonium chloride, water,and brine, dried over magnesium sulfate and then, concentrated. Theresidue thus obtained was subjected to flash chromatography on a silicagel column, and the fraction obtained from the hexane:ethyl acetate=1:1eluate was concentrated. The solid thus obtained was recrystallized fromethyl acetate-hexane, whereby the title compound (71.5 mg, 0.163 mmol,81%) was obtained as colorless plate crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.50-1.67 (2H, m), 2.09-2.20 (1H, m),2.50-2.59 (1H, m), 2.95 (3H, s), 3.12-3.21 (2H, m), 4.30 (1H, t, J=6.3Hz), 4.56 (1H, dd, J=10.7, 4.4 Hz), 6.84 (1H, td, J=9.0, 4.6 Hz),6.96-7.03 (1H, m), 7.23-7.28 (1H, m), 7.39 (2H, d, J=8.0 Hz), 7.53 (2H,d, J=8.0 Hz).

IR (ATR) cm⁻¹: 3269, 1585, 1498, 1308, 1252, 1217, 1140, 1090, 1082,976, 870, 787, 750, 627, 517, 467.

mp: 128° C.

MS m/z: 438 (M⁺+H).

Anal. calcd for C₁₇H₁₈ClF₂NO₄S₂: C, 46.63; H, 4.14; Cl, 8.10; F, 8.68;N, 3.20; S, 14.64. Found: C, 46.62; H, 4.08; Cl, 8.15; F, 8.69; N, 3.27;S, 14.71.

Example 2312-[1-(4-Chlorophenylsulfonyl)-5-fluoropentyl]-1,4-difluorobenzene

The 5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-1-pentanol (152mg, 0.404 mmol) obtained in Example 29 was dissolved in dichloromethane(4 ml), followed by the addition of N-methylmorpholine (58.0 μl, 0.528mmol) and methanesulfonyl chloride (37.8 μl, 0.487 mmol) at 0° C. Theresulting mixture was stirred at 0° C. for 2 hours, and then at roomtemperature for further 3 hours. After dilution with dichloromethane,the mixture was successively washed with a saturated aqueous solution ofammonium chloride, water and brine, dried over magnesium sulfate andthen concentrated. The residue thus obtained was dissolved intetrahydrofuran (4 ml). To the resulting solution was added atetrahydrofuran solution (1.0M, 0.487 ml, 0.487 mmol) oftetrabutylammonium fluoride at room temperature. The resulting mixturewas stirred at 60° C. for 4 hours. After cooling to room temperature anddilution with ethyl acetate, the mixture was washed with water andbrine, dried over magnesium sulfate and then, concentrated. The residuethus obtained was subjected to flash chromatography on a silica gelcolumn, and the fraction obtained from the hexane:ethyl acetate=9:1eluate was concentrated. The solid thus obtained was recrystallized fromhexane, whereby the title compound (30.3 mg, 0.0804 mmol, 20%) wasobtained as colorless plate crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.34-1.42 (2H, m), 1.64-1.80 (2H, m),2.09-2.20 (1H, m), 2.45-2.53 (1H, m), 4.39 (2H, dt, J=47.1, 5.9 Hz),4.52 (1H, dd, J=11.2, 2.9 Hz), 6.84 (1H, td, J=9.0, 4.4 Hz), 6.96-7.02(1H, m), 7.23-7.28 (1H, m), 7.38 (2H, d, J=8.5 Hz), 7.53 (2H, d, J=8.5Hz)

mp: 77-78° C.

IR (ATR) cm⁻¹: 2941, 1585, 1495, 1429, 1396, 1321, 1279, 1242, 1186,1149, 1092, 1084, 962, 874, 829, 777, 752, 710, 633, 557, 536, 474.

MS m/z: 377 (M⁺+H).

Anal. calcd for C₁₇H₁₆ClF₃O₂S: C, 54.19; H, 4.28; Cl, 9.41; F, 15.13; S,8.51. Found: C, 54.27; H, 4.22; Cl, 9.44; F, 14.90; S, 8.68.

Example 2322-[1-[(4-Chlorophenyl)sulfonyl]-1-methylethyl]-1,4-difluorobenzene

Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57Mhexane solution, 450 μl, 0.707 mmol) was added to a tetrahydrofuransolution (4 ml) of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.660mmol) obtained in Example 5. After stirring for 5 minutes, iodomethane(103 μl, 1.65 mmol) was added. The resulting mixture was stirred forfurther 10 minute, and then, n-butyl lithium (a 1.57M hexane solution,474 μl, 0.744 mmol) was added. After the temperature of the reactionmixture was elevated to room temperature, stirring was conducted for 2hours. Water was added, followed by extraction with ethyl acetate. Theextracts were combined, washed with brine, dried over magnesium sulfateand then, concentrated. The residue thus obtained was recrystallizedfrom ethyl acetate-hexane, whereby the title compound (163 mg, 0.492mmol, 75%) was obtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.87 (3H, s), 1.88 (3H, s), 6.86 (1H, ddd,J=11.9, 9.0, 4.9 Hz), 6.98-7.05 (1H, m), 7.10 (1H, ddd, J=9.8, 6.6, 3.4Hz), 7.39 (2H, d, J=8.5 Hz), 7.44 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 1574, 1489, 1475, 1412, 1304, 1219, 1184, 1155, 1124,1068, 1011, 887, 867, 827, 756, 712, 660, 623, 600, 571, 532, 511, 474,432.

mp: 147-148° C.

MS m/z: 331 (M⁺+H).

Anal. calcd for C₁₅H₁₃ClF₂O₂S: C, 54.47; H, 3.96; Cl, 10.72; F, 11.49;S, 9.69. Found: C, 54.39; H, 3.92; Cl, 10.68; F, 11.51; S, 9.78.

Example 2332-[1-[(4-Chlorophenyl)sulfonyl]cyclopropyl]-1,4-difluorobenzene

Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57Mhexane solution, 600 μl, 0.942 mmol) was added to a tetrahydrofuransolution (4 ml) of the3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)-1-propanol (300 mg,0.865 mmol) obtained in Example 207. After stirring for 5 minutes,methanesulfonyl chloride (70.6 μl, 0.908 mmol) was added. The resultingsolution was stirred for further 5 minutes and then, n-butyl lithium (a1.57M hexane solution, 601 μl, 0.944 mmol) was added thereto. Thetemperature of the reaction mixture was elevated to room temperature, atwhich stirring was conducted for 18 hours. After cooling to −78° C.,n-butyl lithium (a 1.57M hexane solution, 400 μl, 0.255 mmol) was added.The reaction mixture was stirred at room temperature for 3 hours. Waterwas added, followed by extraction with ethyl acetate. The extracts werecombined, washed with brine, dried over magnesium sulfate and then,concentrated. The residue thus obtained was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate=19:1 eluate was concentrated. The solid thusobtained was recrystallized from ethyl acetate-hexane, whereby the titlecompound (161 mg, 0.489 mmol, 57%) was obtained as colorless platecrystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.31 (2H, dd, J=7.6, 5.1 Hz), 2.02 (2H, dd,J=7.6, 5.1 Hz), 6.83 (1H, td, J=9.0, 4.4 Hz), 6.97-7.03 (1H, m), 7.06(1H, ddd, J=8.3, 5.4, 3.2 Hz), 7.41 (2H, d, J=8.6 Hz), 7.49 (2H, d,J=8.6 Hz).

IR (ATR) cm⁻¹: 3089, 1583, 1496, 1477, 1429, 1308, 1279, 1252, 1211,1184, 1142, 1086, 1012, 893, 827, 769, 758, 737, 663, 625, 596, 559,546, 492, 476, 451, 411.

mp: 177-179° C.

MS m/z: 329 (M⁺+H).

Anal. calcd for C₁₅H₁₁ClF₂O₂S: C, 54.80; H, 3.37; Cl, 10.78; F, 11.56;S, 9.75. Found: C, 54.72; H, 3.31; Cl, 10.71; F, 11.58; S, 9.87.

Referential Example 38 5-(t-Butyldimethylsilyloxy)pentanal

Under a nitrogen atmosphere and at 0° C., dimethylsulfoxide (7.81 ml,110 mmol), triethylamine (9.60 ml, 69.0 mmol), and a sulfurtrioxide-pyridine complex (4.39 g, 27.6 mmol) were added to adichloromethane solution (80 ml) of 5-(t-butyldimethylsilyloxy)pentanol(3.00 g, 13.8 mmol). The resulting mixture was stirred at 0° C. for 30minutes and then, at room temperature for further 3 hours. After coolingto 0° C., a saturated aqueous ammonium chloride solution was added.Dichloromethane was distilled off under reduced pressure. To the residuewas added ethyl acetate. After the water layer was separated, theorganic layer was washed with water and brine, dried over magnesiumsulfate and then, concentrated. The residue thus obtained was subjectedto chromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate=20:1 eluate was concentrated, whereby the titlecompound (2.42 g, 11.2 mmol, 81%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.05 (3H, s), 0.05 (3H, s), 0.89 (9H, s),1.50-1.60 (2H, m), 1.65-1.75 (2H, m), 2.46 (2H, t, J=6.8 Hz), 3.63 (2H,t, J=6.3 Hz), 9.77 (1H, s).

MS m/z: 217 (M⁺+H).

Example 2346-(t-Butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-hexanol(Isomer 234-A and Isomer 234-B)

Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57Mhexane solution, 1.40 ml, 2.20 mmol) was added to a dimethoxyethanesolution (10 ml) of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (606 mg, 2.00mmol) obtained in Example 5. After dropwise addition of5-(t-butyldimethylsilyloxy)pentanal (475 mg, 2.20 mmol), the resultingmixture was stirred at room temperature for 3 days. The reaction mixturewas cooled to 0° C. To the resulting mixture were added water and then,ethyl acetate. After the water layer was separated, the organic layerwas washed successively with an aqueous ammonium chloride solution,water and brine, dried over magnesium sulfate and then, concentrated.The residue thus obtained was subjected to flash chromatography on asilica gel column, and the fraction obtained from the hexane:ethylacetate=10:1 eluate was concentrated, whereby the title

Isomer 234-A (low polarity) (43.1 mg, 0.102 mmol, 5%) and the titleIsomer 234-B (high polarity) (120 mg, 0.231 mmol, 12%) were obtained,each as a colorless oil.

Isomer 234-A

¹H-NMR (400 MHz, CDCl₃) δ: 0.00 (3H, s), 0.00 (3H, s), 0.85 (9H, s),1.25-1.70 (6H, m), 3.12 (1H, d, J=3.2 Hz), 3.55 (2H, t, J=5.9 Hz), 4.48(1H, s), 4.83-4.88 (1H, m), 6.83 (1H, td, J=9.0, 4.6 Hz), 6.95-7.02 (1H,m), 7.39 (2H, d, J=8.5 Hz), 7.57 (2H, d, J=8.5 Hz), 7.84 (1H, ddd,J=9.0, 5.9, 3.4 Hz).

MS m/z: 519 (M⁺+H)

Isomer 234-B

¹H-NMR (400 MHz, CDCl₃) δ: −0.04 (3H, s), −0.01 (3H, s), 0.85 (9H, s),1.30-1.54 (6H, m), 3.50-3.57 (2H, m), 3.81 (1H, br s), 4.58-4.80 (2H,m), 6.84 (1H, td, J=9.0, 4.6 Hz), 6.96-7.06 (1H, m), 7.15-7.27 (1H, m),7.39 (2H, d, J=8.5 Hz), 7.52 (2H, d, J=8.5 Hz).

MS m/z: 519 (M⁺+H).

Example 2356-[(4-Chlorophenyl)sulfonyl]-6-(2,5-difluorophenyl)-1,5-hexanediol

The6-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-hexanol(Isomer 234-A) (42.0 mg, 0.0809 mmol) obtained in Example 234 wasdissolved in tetrahydrofuran (2 ml), followed by the addition ofhydrogen fluoride-pyridine (0.2 ml). The resulting mixture was stirredat room temperature for 6 hours. The solution was diluted with ethylacetate, washed with water and brine, dried over magnesium sulfate. Thesolid thus obtained was recrystallized from ethyl acetate-hexane,whereby the title compound (16.7 mg, 0.0412 mmol, 51%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.25-1.70 (7H, m), 3.15 (1H, s), 3.55-3.65(2H, m), 4.49 (1H, s), 4.86-4.90 (1H, m), 6.85 (1H, td, J=9.0, 4.4 Hz),6.97-7.03 (1H, m), 7.40 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.8 Hz), 7.85(1H, ddd, J=9.0, 5.9, 3.4 Hz).

IR (ATR) cm⁻¹: 3232, 1576, 1491, 1396, 1306, 1236, 1217, 1147, 1093,1012, 891, 814, 756, 719, 615, 548, 467.

mp: 108-109° C.

MS m/z: 405 (M⁺+H).

FAB-MS: 405.0756 (Calcd for C₁₈H₁₉ClF₂O₄S: 405.0739).

Anal. calcd for C₁₈H₁₉ClF₂O₄S.0.5H₂O: C, 52.24; H, 4.87; S, 7.75. Found:C, 52.33; H, 4.84; S, 7.83.

Example 2366-[(4-Chlorophenyl)sulfonyl]-6-(2,5-difluorophenyl)-1,5-hexanediol

The6-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-hexanol(Isomer 234-B) (120 mg, 0.231 mmol) obtained in Example 234 wasdissolved in tetrahydrofuran (5 ml), followed by the addition ofhydrogen fluoride-pyridine (0.5 ml). The resulting mixture was stirredat room temperature for 20 hours. The reaction mixture was diluted withethyl acetate, washed successively with water, a saturated aqueoussolution of sodium bicarbonate, and brine, dried over magnesium sulfateand then, concentrated. The residue thus obtained was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate=1:1 eluate was concentrated. The solid thusobtained was recrystallized from ethyl acetate-hexane, whereby the titlecompound (51.3 mg, 0.127 mmol, 55%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.25-1.67 (7H, m), 3.53-3.63 (2H, m), 3.91(1H, br s), 4.59-4.78 (2H, m), 6.85 (1H, td, J=9.0, 4.4 Hz), 6.96-7.03(1H, m), 7.16-7.27 (1H, br m), 7.39 (2H, d, J=8.5 Hz), 7.52 (2H, d,J=8.5 Hz). IR (ATR) cm⁻¹: 3496, 2956, 1579, 1496, 1425, 1392, 1305,1275, 1180, 1144, 1080, 1011, 966, 922, 833, 810, 756, 737, 650, 536,521, 461.

mp: 105-107° C.

MS m/z: 405 (M⁺+H).

Anal. calcd for C₁₈H₁₉ClF₂O₄S: C, 53.40; H, 4.73; Cl, 8.76; F, 9.39; S,7.92. Found: C, 53.20; H, 4.61; Cl, 8.77; F, 9.20; S, 8.03.

Referential Example 39 4-(t-butyldimethylsilyloxy)-2-butanol

In N,N-dimethylformamide (30 ml) was dissolved 1,3-butanediol (3.00 g,33.3 mmol), followed by the dropwise addition of anN,N-dimethylformamide solution (30 ml) of imidazole (2.72 g, 40.0 mmol)and t-butylchlorodimethylsilane (5.29 g, 35.0 mmol). After stirring atroom temperature for 24 hours, ether was added to the reaction mixtureand the white solid thus precipitated was filtered off. The resultingether solution was washed with water and brine, dried over magnesiumsulfate and then concentrated. The residue thus obtained was subjectedto flash chromatography on a silica gel column, and the fractionobtained from the hexane:ethyl acetate=5:1 eluate was concentrated,whereby the title compound (5.43 g, 26.6 mmol, 80%) was obtained as acolorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.08 (6H, s), 0.90 (9H, d, J=1.0 Hz), 1.19(3H, d, J=6.4 Hz), 1.59-1.73 (2H, m), 3.78-3.93 (2H, m), 3.98-4.07 (1H,br m).

MS m/z: 205 (M⁺+H).

Example 2372-[4-(t-Butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-2-methylbutyl]-1,4-difluorobenzene(Compound A (Isomer A) and Compound A (Isomer B)), and2-[4-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]pentyl]-1,4-difluorobenzene(Compound B)

Compound A Compound B

Under a nitrogen atmosphere, the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (303 mg, 1.00mmol) obtained in Example 5 and 4-(tert-butyldimethylsilyloxy)-2-butanol(408 mg, 2.00 mmol) were dissolved in toluene (4 ml). After addition ofcyanomethylenetri-n-butylphosphorane (482 mg, 2.00 mmol), the resultingmixture was heated under reflux for 15 hours under a nitrogenatmosphere. The reaction mixture was then concentrated. The residue thusobtained was separated and purified by flash chromatography on a silicagel column (hexane:ethyl acetate=50:1), whereby obtained were the titlecompound A (Isomer A) (low polarity) (109 mg, 0.222 mmol, 22%), thetitle compound A (Isomer B) (high polarity) (102 mg, 0.209 mmol, 21%),and the title compound B (234 mg, 0.479 mmol, 48%), each as a colorlessoil.

Compound A (Isomer A)

¹H-NMR (400 MHz, CDCl₃) δ: 0.05 (3H, s), 0.05 (3H, s), 0.89 (9H, s),1.14 (3H, d, J=6.8 Hz), 1.38-1.47 (1H, m), 1.79-1.89 (1H, m), 2.91-3.02(1H, m), 3.63-3.73 (2H, m), 4.56 (1H, d, J=5.9 Hz), 6.81 (1H, td, J=9.0,4.6 Hz), 6.92-6.98 (1H, m), 7.34 (2H, d, J=8.3 Hz), 7.51-7.57 (1H, m),7.55 (2H, d, J=8.3 Hz).

MS m/z: 489 (M⁺+H).

Compound A (Isomer B)

¹H-NMR (400 MHz, CDCl₃) δ: −0.01 (3H, s), 0.00 (3H, s), 0.85-0.93 (9H,m), 1.19-1.28 (1H, m), 1.38 (3H, d, J=6.6 Hz), 1.64-1.73 (1H, m),2.78-2.88 (1H, m), 3.61 (2H, dd, J=7.6, 4.9 Hz), 4.46 (1H, d, J=9.0 Hz),6.72 (1H, td, J=9.0, 4.4 Hz), 6.87-6.93 (1H, m), 7.30 (2H, d, J=8.3 Hz),7.34-7.41 (1H, m), 7.49 (2H, d, J=8.3 Hz).

MS m/z: 489 (M⁺+H).

Compound B

¹H-NMR (400 MHz, CDCl₃) δ: −0.01 (1.5H, s), 0.01 (1.5H, s), 0.02 (1.5H,s), 0.04 (1.5H, s), 0.84 (4.5H, m), 0.86 (4.5H, m), 1.04-1.10 (3H, m),1.15-1.40 (2H, m), 1.99-2.11 (0.5H, m), 2.11-2.22 (0.5H, m), 2.35-2.53(1H, m), 3.72-3.82 (1H, m), 4.44-4.52 (1H, m), 6.82-6.88 (1H, m),6.93-7.02 (1H, m), 7.16-7.26 (1H, m), 7.37-7.42 (2H, m), 7.51-7.58 (2H,m).

MS m/z: 489 (M⁺+H).

Example 2384-(4-Chlorophenylsulfonyl)-4-(2,5-difluorophenyl)-3-methyl-1-butanol

The2-[4-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-2-methylbutyl]-1,4-difluorobenzene(Compound A (Isomer A)) (109 mg, 0.223 mmol) obtained in Example 237 wasdissolved in tetrahydrofuran (3 ml), followed by the addition ofhydrogen fluoride-pyridine (0.5 ml). The resulting mixture was stirredat room temperature for 5 hours. The reaction mixture was diluted withethyl acetate, washed with water, a saturated aqueous solution of sodiumbicarbonate, and brine, and dried over magnesium sulfate. The solid thusobtained was recrystallized from ethyl acetate-hexane, whereby the titlecompound (61.1 mg, 0.163 mmol, 73%) was obtained as colorless columnarcrystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.08 (3H, d, J=7.1 Hz), 1.59-1.62 (1H, m),1.74-1.84 (1H, m), 1.96-2.05 (1H, m), 2.93-3.05 (1H, m), 3.75-3.89 (2H,m), 4.68 (1H, d, J=6.8 Hz), 6.77 (1H, td, J=9.0, 4.6 Hz), 6.91-6.97 (1H,m), 7.33 (2H, d, J=8.3 Hz), 7.45-7.51 (1H, m), 7.51 (2H, d, J=8.3 Hz).

IR (ATR) cm⁻¹: 3527, 2935, 2897, 1583, 1487, 1315, 1267, 1232, 1188,1144, 1086, 1068, 1049, 1012, 889, 864, 829, 789, 750, 715, 654, 611,551, 490, 467.

mp: 111-112° C.

MS m/z: 375 (M⁺+H).

Anal. calcd for C₁₇H₁₇ClF₂O₃S: C, 54.47; H, 4.57; Cl, 9.46; F, 10.14; S,8.55. Found: C, 54.44; H, 4.55; Cl, 9.44; F, 10.08; S, 8.75.

Example 2394-(4-Chlorophenylsulfonyl)-4-(2,5-difluorophenyl)-3-methyl-1-butanol

The2-[4-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-2-methylbutyl]-1,4-difluorobenzene(Compound A (Isomer B)) (102 mg, 0.209 mmol) obtained in Example 237 wasdissolved in tetrahydrofuran (3 ml), followed by the addition ofhydrogen fluoride-pyridine (0.5 ml). The resulting mixture was stirredat room temperature for 15 hours. The reaction mixture was diluted withethyl acetate, washed with water and brine, and then dried overmagnesium sulfate. The solid thus obtained was recrystallized from ethylacetate-hexane, whereby the title compound (36.1 mg, 0.0963 mmol, 46%)was obtained as colorless columnar crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.23-1.40 (2H, m), 1.35 (3H, d, J=6.6 Hz),1.81-1.90 (1H, m), 2.84-2.93 (1H, m), 3.63-3.78 (2H, m), 4.51 (1H, d,J=8.1 Hz), 6.75 (1H, td, J=9.0, 4.6 Hz), 6.89-6.96 (1H, m), 7.31 (2H, d,J=8.5 Hz), 7.40-7.47 (1H, m), 7.51 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3525, 2954, 1655, 1493, 1477, 1427, 1394, 1306, 1279,1240, 1180, 1144, 1080, 1055, 1014, 943, 887, 822, 754, 712, 665, 609,559, 542, 453.

mp: 65-67° C.

MS m/z: 375 (M⁺+H).

Anal. calcd for C₁₇H₁₇ClF₂O₃S.0.5H₂O: C, 53.20; H, 4.73; Cl, 9.24; F,9.90; S, 8.35. Found: C, 53.17; H, 4.86; Cl, 9.29; F, 10.00; S, 8.50.

Example 2401-[(4-Chlorophenyl)sulfonyl1-(2,5-difluorophenyl)]-4-pentanol (Isomer240-A and Isomer 240-B)

The2-[4-(tert-butyldimethylsilyloxy)-1-(4-chlorophenylsulfonyl)pentyl]-1,4-difluorobenzene(Compound B) (230 mg, 0.470 mmol) obtained in Example 237 was dissolvedin tetrahydrofuran (4 ml), followed by the addition of a tetrahydrofuransolution (1.0M, 0.564 ml, 0.564 mmol) of tetrabutylammonium fluoride.The resulting mixture was stirred at room temperature for 18 hours. Thereaction mixture was diluted with ethyl acetate, washed with water andbrine, dried over magnesium sulfate and then, concentrated. The residuethus obtained was separated and purified by flash chromatography on asilica gel column (hexane:ethyl acetate=2:1) to give a low-polarityisomer and a high-polarity isomer, each as a white solid. The resultinglow-polarity isomer was recrystallized from hexane, whereby the titleIsomer 240-A (low polarity) (48.0 mg, 0.128 mmol, 27%) was obtained ascolorless needle crystals. On the other hand, the resultinghigh-polarity isomer was recrystallized from hexane, whereby the title

Isomer 240-B (high polarity) (48.8 mg, 0.130 mmol, 28%) was obtained ascolorless needle crystals.

Isomer 240-A

¹H-NMR (400 MHz, CDCl₃) δ: 1.17 (3H, d, J=6.1 Hz), 1.28-1.48 (3H, m),2.18-2.29 (1H, m), 2.47-2.56 (1H, m), 3.77-3.85 (1H, m), 4.53-4.58 (1H,m), 6.83 (1H, td, J=9.0, 4.4 Hz), 6.95-7.01 (1H, m), 7.22-7.28 (1H, m),7.38 (2H, d, J=8.5 Hz), 7.53 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3370, 3087, 2925, 1587, 1574, 1496, 1475, 1423, 1396,1311, 1279, 1234, 1178, 1149, 1128, 1086, 1014, 949, 874, 827, 789, 760,735, 710, 679, 631, 584, 559, 525, 469.

mp: 97-98° C.

MS m/z: 375 (M⁺+H).

Anal. calcd for C₁₇H₁₇ClF₂NO₃S: C, 54.47; H, 4.57; Cl, 9.46; F, 10.14;S, 8.55. Found: C, 54.35; H, 4.69; Cl, 9.64; F, 10.31; S, 8.80.

Isomer 240-B

¹H-NMR (400 MHz, CDCl₃) δ: 1.17 (3H, d, J=6.1 Hz), 1.29-1.45 (3H, m),2.07-2.18 (1H, m), 2.58-2.67 (1H, m), 3.77-3.85 (1H, m), 4.59 (1H, dd,J=11.2, 2.9 Hz), 6.84 (1H, td, J=9.0, 4.4 Hz), 6.95-7.02 (1H, m),7.23-7.27 (1H, m), 7.38 (2H, d, J=8.5 Hz), 7.54 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3504, 3390, 2960, 2925, 1585, 1493, 1475, 1427, 1396,1302, 1275, 1227, 1174, 1146, 1082, 1036, 1014, 823, 752, 723, 708, 625,555, 530, 463.

mp: 89° C.

MS m/z: 375 (M⁺+H).

Anal. calcd for C₁₇H₁₇ClF₂NO₃S: C, 54.47; H, 4.57; Cl, 9.46; F, 10.14;S, 8.55. Found: C, 54.25; H, 4.46; Cl, 9.51; F, 10.41; S, 8.66.

Example 241 t-butylN-[5-[(4-Chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)pentyl]-N-methylsulfonylcarbamate

The 5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-1-pentanol (115mg, 0.307 mmol) obtained in Example 29, t-butylN-methylsulfonylcarbamate (120 mg, 0.614 mmol), and triphenylphosphine(163 mg, 0.614 mmol) were dissolved in tetrahydrofuran (3 ml). At roomtemperature, diisopropyl azodicarboxylate (120 μl, 0.614 mmol) was addedto the resulting solution. After stirring the resulting mixture for 18hours at room temperature, the reaction mixture was diluted with ethylacetate, washed with water and brine, dried over magnesium sulfate andthen concentrated. The residue thus obtained was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate=3:1 eluate was concentrated, whereby the titlecompound (168 mg, 0.304 mmol, 99%) was obtained as a colorless amorphoussubstance.

¹H-NMR (400 MHz, CDCl₃) δ: 1.22-1.35 (2H, m), 1.50 (9H, m), 1.58-1.73(2H, m), 2.08-2.18 (1H, m), 2.39-2.49 (1H, m), 3.22 (3H, s), 3.59 (2H,ddd, J=8.1, 6.6, 3.9 Hz), 4.53 (1H, dd, J=11.2, 2.9 Hz), 6.83 (1H, td,J=9.0, 4.4 Hz), 6.95-7.01 (1H, m), 7.22-7.27 (1H, m), 7.39 (2H, d, J=8.5Hz), 7.54 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 1722, 1583, 1496, 1350, 1321, 1281, 1149, 1087, 1012,966, 831, 754, 710, 629, 517.

MS m/z: 452 (M⁺-Boc), 496 (M⁺-t-Bu), 574 (M⁺+Na).

FAB-MS: 574.0932 (Calcd for C₂₃H₂₈ClF₂NO₆S₂Na: 574.0912).

Example 242N-[5-[(4-Chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)pentyl]methanesulfonamide

In dichloromethane (4 ml) was dissolved t-butylN-[5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)pentyl]-N-methylsulfonylcarbamate(108 mg, 0.196 mmol), followed by the addition of trifluoroacetic acid(1 ml) at room temperature. The resulting mixture was stirred at roomtemperature for 3 hours. The reaction mixture was diluted withdichloromethane, washed successively with water, a saturated aqueoussolution of sodium bicarbonate, and brine, dried over magnesium sulfateand then concentrated. The residue thus obtained was subjected to flashchromatography on a silica gel column, and the fraction obtained fromthe hexane:ethyl acetate=1:1 eluate was concentrated, whereby the solidthus obtained was recrystallized from ethyl acetate-hexane, whereby thetitle compound (75.5 mg, 0.167 mmol, 85%) was obtained as a whitepowder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.28-1.38 (2H, m), 1.55-1.68 (2H, m),2.06-2.18 (1H, m), 2.43-2.52 (1H, m), 2.92 (3H, s), 3.09 (2H, dd,J=13.4, 6.8 Hz), 4.15-4.24 (1H, m), 4.51 (1H, dd, J=11.5, 3.4 Hz), 6.84(1H, td, J=9.0, 4.4 Hz), 6.96-7.03 (1H, m), 7.22-7.28 (1H, m), 7.39 (2H,d, J=8.5 Hz), 7.52 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3219, 2871, 1583, 1495, 1425, 1300, 1248, 1167, 1144,1084, 1068, 978, 893, 835, 752, 725, 706, 629, 545, 525, 471.

mp: 106-107° C.

MS m/z: 452 (M⁺+H).

Anal. calcd for C₁₈H₂₀ClF₂NO₄S₂: C, 47.84; H, 4.46; Cl, 7.84; F, 8.41;N, 3.10; S, 14.19. Found: C, 47.75; H, 4.47; Cl, 7.94; F, 8.54; N, 3.14;S, 14.25.

Example 243 t-ButylN-[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-3-methylbutyl]-N-methylsulfonylcarbamate

The4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-3-methyl-1-butanol(97.2 mg, 0.259 mmol) obtained in Example 239, t-butylN-methylsulfonylcarbamate (101 mg, 0.518 mmol) and triphenylphosphine(138 mg, 0.518 mmol) were dissolved in tetrahydrofuran (3 ml), followedby the addition of diisoopropyl azodicarboxylate (102 μl, 0.518 mmol) atroom temperature. The reaction mixture was stirred at room temperaturefor 18 hours. The reaction mixture was diluted with ethyl acetate,washed with a saturated aqueous solution of ammonium chloride, water andbrine, dried over magnesium sulfate and then concentrated. The residuethus obtained was subjected to flash chromatography on a silica gelcolumn, and the fraction obtained from the hexane:ethyl acetate=3:2eluate was concentrated, whereby the title compound (136 mg, 0.246 mmol,95%) was obtained as a colorless amorphous substance.

¹H-NMR (400 MHz, CDCl₃) δ: 1.33 (3H, d, J=6.8 Hz), 1.35-1.45 (1H, m),1.52 (9H, s), 1.99-2.08 (1H, m), 2.70-2.78 (1H, m), 3.27 (3H, s),3.65-3.76 (2H, m), 4.45 (1H, d, J=7.6 Hz), 6.77 (1H, td, J=9.0, 4.6 Hz),6.91-6.97 (1H, m), 7.32 (2H, d, J=8.5 Hz), 7.38-7.45 (1H, m), 7.50 (2H,d, J=8.5 Hz).

MS m/z: 552 (M⁺+H), 574 (M⁺+Na).

FAB-MS: 552.1070 (Calcd for C₂₃H₂₉ClF₂NO₆S₂: 552.1093), 574.0875 (Calcdfor C₂₃H₂₈ClF₂NO₆S₂Na: 574.0912).

Example 244N-[4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-3-methylbutyl]methanesulfonamide

The t-butylN-[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-3-methylbutyl]-N-methylsulfonylcarbamate(136 mg, 0.246 mmol) obtained in Example 243 was dissolved indichloromethane (4 ml), followed by the addition of trifluoroacetic acid(1 ml) at room temperature. After stirring at room temperature for 6hours, the reaction mixture was diluted with dichloromethane, washedsuccessively with water, a saturated aqueous solution of sodiumbicarbonate, and brine, dried over magnesium sulfate and then,concentrated. The solid thus obtained was recrystallized from ethylacetate-hexane, whereby the title compound (99.5 mg, 0.220 mmol, 89%)was obtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.27 (3H, d, J=6.8 Hz), 1.35-1.44 (1H, m),1.95-2.05 (1H, m), 2.82-2.88 (1H, m), 2.95 (3H, s), 3.10-3.19 (1H, m),3.22-3.30 (1H, m), 4.21-4.28 (1H, br m), 4.49 (1H, t, J=6.6 Hz), 6.81(1H, td, J=9.0, 4.4 Hz), 6.93-7.00 (1H, m), 7.34 (2H, d, J=8.5 Hz),7.42-7.48 (1H, m), 7.52 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3251, 3076, 1581, 1495, 1473, 1317, 1244, 1140, 881, 837,781, 750, 729, 710, 665, 617, 553, 521, 465.

mp: 163° C.

MS m/z: 452 (M⁺+H).

Anal. calcd for C₁₈H₂₀ClF₂NO₄S₂: C, 47.84; H, 4.46; Cl, 7.84; F, 8.41;N, 3.10; S, 14.19. Found: C, 47.88; H, 4.45; Cl, 7.91; F, 8.51; N, 3.16;S, 14.23.

Example 245N-[3-(4-Chlorophenylsulfonyl)-3-(2,5-difluorophenyl)propyl]methanesulfonamide

The 3-(4-chlorophenylsulfonyl)-3-(2,5-difluorophenyl)-1-propanol (120mg, 0.307 mmol) obtained in Example 207, t-butylN-methylsulfonylcarbamate (101 mg, 0.519 mmol), and triphenylphosphine(138 mg, 0.519 mmol) were dissolved in tetrahydrofuran (3 ml), followedby the addition of diisopropyl azodicarboxylate (102 μl, 0.519 mmol) atroom temperature. The resulting mixture was stirred at room temperaturefor 18 hours. The reaction mixture was diluted with ethyl acetate,washed with water and brine, dried over magnesium sulfate and then,concentrated. The residue thus obtained was subjected to chromatographyon a silica gel column (hexane:ethyl acetate=4:1) to remove thehigh-polarity byproduct. The crude product thus obtained was dissolvedin dichloromethane (4 ml), followed by the addition of trifluoroaceticacid (2 ml). The resulting mixture was stirred at room temperature for 6hours. The reaction mixture was diluted with dichloromethane, washedsuccessively with water, a saturated aqueous solution of sodiumbicarbonate, and brine, dried over magnesium sulfate and then,concentrated. The solid thus obtained was recrystallized from ethylacetate-hexane, whereby the title compound (90.2 mg, 0.213 mmol, 62%)was obtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 2.29-2.39 (1H, m), 2.69-2.78 (1H, m), 2.93(3H, s), 3.10-3.20 (1H, m), 3.35-3.44 (1H, m), 4.44-4.50 (1H, br m),4.74 (1H, dd, J=9.0, 6.1 Hz), 6.84 (1H, td, J=9.0, 4.6 Hz), 6.97-7.04(1H, m), 7.23 (1H, ddd, J=8.5, 5.4, 3.2 Hz), 7.39 (2H, d, J=8.5 Hz),7.52 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3257, 3087, 2947, 1587, 1496, 1475, 1308, 1090, 1279,1147, 1086, 1014, 962, 879, 827, 760, 737, 679, 621, 523, 463, 413.

mp: 131-134° C.

MS m/z: 424 (M⁺+H).

Anal. calcd for C₁₆H₁₆ClF₂NO₄S₂: C, 45.34; H, 3.80; Cl, 8.36; F, 8.96;N, 3.30; S, 15.13. Found: C, 45.22; H, 3.67; Cl, 8.34; F, 8.98; N, 3.38;S, 15.16.

Referential Example 40 4-(t-Butyldiphenylsilyloxy)-2-buten-1-ol

In a dichloromethane/N,N-dimethylformamide (200 ml/200 ml) mixture weredissolved 2-buten-1,4-diol (10.0 g, 113 mmol) and imidazole (4.70 g,69.0 mmol), followed by the dropwise addition oft-butylchlorodiphenylsilane (30.0 ml, 115 mmol) at room temperature.After completion of the dropwise addition, the mixture was stirred atroom temperature for 4 days. The residue obtained by concentrating thereaction mixture under reduced pressure was added with diethyl ether.From the resulting mixture, the insoluble matter was filtered off. Thediethyl ether layer was washed with water and then, the organic layerwas dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The residue wassubjected to flash silica gel chromatography, and the fraction obtainedfrom the hexane:ethyl acetate=2:1 eluate was concentrated under reducedpressure, whereby the title compound (15.3 g, 46.9 mmol, 42%) wasobtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.06 (9H, s), 4.01 (0.5H, br d, J=6.1 Hz),4.15 (1.5H, br d, J=4.9 Hz), 4.18-4.26 (1.5H, m), 4.26 (0.5H, dm, J=5.9Hz), 5.60-5.75 (1H, m), 5.78 (3H, dm, J=15.4 Hz), 7.34-7.52 (5H, m),7.64-7.76 (4H, m).

MS m/z: 327 (M⁺+H).

Example 246(Z)-2-[5-(t-Butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-3-pentenyl]-1,4-difluorobenzene(Isomer 246-A) and(E)-2-[5-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-3-pentenyl]-1,4-difluorobenzene(Isomer 246-B)

Isomer A Isomer B

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (400 mg, 1.32mmol) obtained in Example 5 and 4-(t-butyldiphenylsilyloxy)-2-buten-1-ol(660 mg, 2.02 mmol) were dissolved in toluene (6 ml), followed by theaddition of cyanomethylenetri-n-butylphosphorane (480 mg, 1.99 mmol).Under an argon atmosphere, the resulting mixture was heated under refluxfor 6 hours. After the reaction mixture was allowed to cool down, theresidue obtained by concentrating the reaction mixture under reducedpressure was separated and purified by flash silica gel chromatography(hexane:ethyl acetate=80:1) to give the Isomer 246-A (low polarity) (149mg, 0.244 mmol, 18%) and the title Isomer 246-B (high polarity) (468 mg,0.766 mmol, 58%), each as a colorless oil.

Isomer 246-A

¹H-NMR (400 MHz, CDCl₃) δ: 1.04 (9H, s), 2.64-2.78 (1H, m), 2.95-3.08(1H, m), 4.09 (1H, ddm, J=13.5, 5.6 Hz), 4.15 (1H, ddm, J=13.5, 6.3 Hz),4.45 (1H, ddm, J=11.0, 3.4 Hz), 5.12 (1H, dtm, J=11.0, 7.3 Hz), 5.62(1H, dtm, J=11.0, 6.3 Hz), 6.80-6.88 (1H, m), 6.90-7.00 (1H, m),7.02-7.21 (1H, m), 7.30-7.60 (10H, m), 7.60-7.72 (4H, m).

IR (ATR) cm⁻¹: 2931, 2856, 1583, 1496, 1473, 1427, 1327, 1151, 1111,1088, 823, 754, 702, 615, 505.

MS m/z: 611 (M⁺+H), 633 (M⁺+Na).

Isomer 246-B

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (9H, s), 2.80-2.92 (1H, m), 3.14-3.26(1H, m), 3.98-4.05 (2H, m), 4.01 (1H, dd, J=11.5, 3.7 Hz), 5.43 (1H,dtm, J=15.0, 7.3 Hz), 5.59 (1H, dtm, J=15.0, 4.4 Hz), 6.75-6.88 (1H, m),6.92-7.01 (1H, m), 7.22-7.50 (9H, m), 7.50-7.65 (6H, m).

IR (ATR) cm⁻¹: 2931, 2856, 1583, 1496, 1427, 1321, 1149, 1111, 1084,1012, 822, 754, 700, 503.

MS m/z: 611 (M⁺+H), 633 (M⁺+Na).

Example 247(Z)-5-[(4-Chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-2-penten-1-ol

In tetrahydrofuran (5 ml) was dissolved(Z)-2-[5-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-3-pentenyl]-1,4-difluorobenzene(Isomer 246-A) (145 mg, 0.237 mmol). After dropwise addition of atetrahydrofuran solution (1.0M, 0.5 ml, 0.5 mmol) of tetrabutylammoniumfluoride, the mixture was stirred at room temperature for 2 hours. Water(0.2 ml) was added to the reaction mixture, followed by concentrationunder reduced pressure. The residue thus obtained was subjected to flashsilica gel chromatography, and the fraction obtained from thehexane:ethyl acetate=2:1 eluate was concentrated under reduced pressureto give a white solid. The white solid was washed with hexane, wherebythe title compound (51 mg, 0.137 mmol, 58%) was obtained as a whitepowder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.35 (1H, br s), 2.82-2.95 (1H, m), 3.22-3.32(1H, m), 4.08-4.18 (1H, m), 4.18-4.28 (1H, m), 4.56 (1H, ddm, J=10.6,4.5 Hz), 5.29 (1H, dtm, J=11.0, 7.5 Hz), 5.67 (1H, dtm, J=11.0, 6.6 Hz),6.77-6.88 (1H, m), 6.92-7.02 (1H, m), 7.22-7.32 (1H, m), 7.39 (2H, d,J=8.7 Hz), 7.54 (2H, d, J=8.7 Hz).

IR (ATR) cm⁻¹: 3560, 3016, 1585, 1495, 1475, 1427, 1396, 1308, 1277,1218, 879, 827, 789, 752, 708, 679, 627, 467, 420.

mp: 60-63° C.

MS m/z: 390 (M⁺+NH₄).

Anal. Calcd for C₁₇H₁₅ClF₂O₃S: C, 54.77; H, 4.06; Cl, 9.51; F, 10.19; S,8.60. Found: C, 54.57; H, 4.08; Cl, 9.41; F, 10.27; S, 8.74.

Example 248(E)-5-[(4-Chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-2-penten-1-ol

The(E)-2-[5-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-3-pentenyl]-1,4-difluorobenzene(Isomer 246-B) (465 mg, 0.761 mmol) obtained in Example 246 wasdissolved in tetrahydrofuran (10 ml), followed by the dropwise additionof a tetrahydrofuran solution (1.0M, 1.5 ml, 1.5 mmol) oftetrabutylammonium fluoride. At room temperature, the mixture wasstirred for 1 hour. After addition of water (0.2 ml), the residueobtained by concentrating the resulting mixture under reduced pressurewas subjected to flash silica gel chromatography, and the fractionobtained from the hexane:ethyl acetate=2:1 eluate was concentrated underreduced pressure to give a white solid. The white solid was washed withhexane, whereby the title compound (225 mg, 0.605 mmol, 80%) wasobtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.21 (1H, br t, J=5.5 Hz), 2.80-2.92 (1H, m),3.18-3.28 (1H, m), 3.96-4.06 (2H, m), 4.57 (1H, ddm, J=11.2, 3.9 Hz),5.44 (1H, dtm, J=15.2, 7.3 Hz), 5.70 (1H, dtm, J=15.2, 5.4 Hz),6.78-6.88 (1H, m), 6.95-7.03 (1H, m), 7.22-7.30 (1H, m), 7.39 (2H, d,J=8.7 Hz), 7.54 (2H, d, J=8.7 Hz).

IR (ATR) cm⁻¹: 3552, 3087, 1583, 1495, 1427, 1396, 1309, 1281, 1219,1186, 1142, 1082, 1016, 984, 874, 831, 775, 756, 710, 619, 553, 534,467. mp: 108-109° C.

MS m/z: 395 (M⁺+Na).

Anal. Calcd for C₁₇H₁₅ClF₂O₃S: C, 54.77; H, 4.06; Cl, 9.51; F, 10.19; S,8.60. Found: C, 54.59; H, 4.03; Cl, 9.53; F, 10.17; S, 8.71.

Referential Example 41 2-[2-(t-Butyldiphenylsilyloxy)ethylthio]ethanol

In dichloromethane (200 ml) were dissolved 2,2′-thiodiethanol (10.0 g,81.8 mmol) and imidazole (4.70 g, 69.0 mmol), followed by the dropwiseaddition of t-butylchlorodiphenylsilane (15.0 ml, 57.7 mmol) at roomtemperature. After completion of the dropwise addition, the reactionmixture was stirred at room temperature for 14 hours. Afterconcentration under reduced pressure, diethyl ether was added to theresidue. Then, the insoluble matter was filtered off. The residueobtained by concentrating the filtrate under reduced pressure wassubjected to flash silica gel chromatography, and the fraction obtainedfrom the hexane:ethyl acetate=3:1 eluate was concentrated under reducedpressure, whereby the title compound (11.3 g, 31.3 mmol, 54%) wasobtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.06 (9H, s), 2.19 (1H, br s), 2.62-2.72 (4H,m), 3.63 (2H, br t, J=5.5 Hz), 3.80 (2H, t, J=6.8 Hz), 7.32-7.52 (6H,m), 7.66-7.75 (4H, m).

IR (ATR) cm⁻¹: 3400, 2929, 2856, 1427, 1105, 822, 735, 700, 611, 503.

MS m/z: 383 (M⁺+Na).

Example 2492-[3-[2-(t-Butyldiphenylsilyloxy)ethylthio]-1-[(4-chlorophenyl)sulfonyl]propyl]-1,4-difluorobenzene

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (900 mg, 2.97mmol) obtained in Example 5 and2-[2-(t-butyldiphenylsilyloxy)ethylthio]ethanol (1.64 g, 4.55 mmol) weredissolved in toluene (20 ml), followed by the addition ofcyanomethylenetri-n-butylphosphorane (1.26 g, 5.22 mmol). Under an argonatmosphere, the resulting mixture was heated under reflux for 9 hours.After the reaction mixture was allowed to cool down,2-[2-(t-butyldiphenylsilyloxy)ethylthio]ethanol (500 mg, 1.39 mmol) andcyanomethylenetri-n-butylphosphorane (400 mg, 1.66 mmol) were addedthereto. Under an argon atmosphere, the mixture was heated under refluxfor 14 hours. After the reaction mixture was allowed to cool down, itwas concentrated under reduced pressure. The residue was subjected toflash silica gel chromatography, and the fraction obtained from thehexane:ethyl acetate=10:1 eluate was concentrated under reducedpressure, whereby the title compound (1.82 g, 2.82 mmol, 95%) wasobtained as a pale yellowish brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.02 (9H, s), 2.20-2.35 (2H, m), 2.50-2.74(4H, m), 3.65-3.80 (2H, m), 4.72-4.80 (1H, m), 6.77-6.85 (1H, m),6.92-7.00 (1H, m), 7.15-7.23 (1H, m), 7.35-7.48 (8H, m), 7.52 (2H, d,J=8.8 Hz), 7.64 (4H, d, J=8.1 Hz).

IR (ATR) cm⁻¹: 2931, 2858, 1583, 1496, 1323, 1149, 1105, 1084, 754, 700,503.

MS m/z: 667 (M⁺+Na).

Example 2502-[3-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propylthio]ethanol

In tetrahydrofuran (30 ml) was dissolved2-[3-[2-(t-butyldiphenylsilyloxy)ethylthio]-1-[(4-chlorophenyl)sulfonyl]propyl]-1,4-difluorobenzene(1.81 g, 2.80 mmol). Under ice cooling, a tetrahydrofuran solution(11.0M, 8.0 ml, 8.0 mmol) of tetrabutylammonium fluoride was addeddropwise to the resulting solution, followed by stirring at roomtemperature for 2 hours. Water (3 ml) was added to the reaction mixture,followed by concentration under reduced pressure. The residue thusobtained was subjected to flash silica gel chromatography, and thefraction obtained from the hexane:ethyl acetate=2:1 eluate wasconcentrated under reduced pressure to give a white solid. The whitesolid was washed with hexane, whereby the title compound (977 mg, 2.40mmol, 86%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.97 (1H, t, J=6.1 Hz), 2.30-2.45 (2H, m),2.60-2.80 (4H, m), 3.60-3.78 (2H, m), 4.81 (1H, dd, J=9.6, 3.5 Hz),6.80-6.90 (1H, m), 6.96-7.05 (1H, m), 7.20-7.30 (1H, m), 7.39 (2H, d,J=8.8 Hz), 7.54 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 3564, 3072, 1583, 1496, 1275, 1144, 1082, 835, 810, 762,627, 534, 480.

mp: 108-110° C.

MS m/z: 424 (M⁺+NH₄)

Anal. Calcd for C₁₇H₁₇ClF₂O₃S₂: C, 50.18; H, 4.21; Cl, 8.71; F, 9.34; S,15.76. Found: C, 49.94; H, 4.20; Cl, 8.84; F, 9.41; S, 15.70.

Example 2514-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)tetrahydrothiopyran

In toluene (50 ml) was dissolved2-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propylthio]ethanol(800 mg, 2.00 mmol), followed by the addition ofcyanomethylenetri-n-butylphosphorane (1.50 g, 6.22 mmol). Under an argonatmosphere, the resulting mixture was heated under reflux for 14 hours.After the reaction mixture was allowed to cool down, it was concentratedunder reduced pressure. The residue was subjected to flash silica gelchromatography, and the fraction obtained from the hexane:ethylacetate-15:1 eluate was concentrated under reduced pressure to give awhite solid. The white solid was washed with hexane, whereby the titlecompound (504 mg, 1.28 mmol, 64%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.46 (2H, br t, J=13.4 Hz), 2.57-2.78 (4H,m), 3.09 (2H, br s), 6.85-6.95 (1H, m), 7.02-7.15 (2H, m), 7.37 (2H, d,J=8.7 Hz), 7.40 (2H, d, J=8.7 Hz).

IR (ATR) cm⁻¹: 2927, 1574, 1495, 1306, 1267, 1147, 1080, 877, 825, 750,710, 619, 561, 472.

mp: 188-190° C.

MS m/z: 389 (M⁺+H).

Anal. Calcd for C₁₇H₁₅ClF₂O₂S₂.0.25H₂O: C, 51.90; H, 3.97; Cl, 9.01; F,9.66; S, 16.30. Found: C, 52.20; H, 3.91; Cl, 9.20; F, 9.85; S, 16.36.

Example 2524-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)tetrahydrothiopyran-1-on

In dichloromethane (30 ml) was dissolved4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)tetrahydrothiopyran(200 mg, 0.508 mmol). Under ice cooling, 3-chloroperbenzoic acid (106mg, 0.614 mmol) was added. After stirring at room temperature for 14hours, the reaction mixture was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel chromatography,and the fraction obtained from the hexane:ethyl acetate=1:1 eluate wasconcentrated under reduced pressure to give a white solid. The whitesolid was washed with diethyl ether, whereby the title compound (163 mg,0.403 mmol, 79%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.30-3.55 (8H, m), 6.85-7.04 (1H, m),7.05-7.20 (2H, m), 7.33 (0.8H, d, J=8.3 Hz), 7.40 (0.8H, d, J=8.3 Hz),7.44 (1.2H, d, J=8.8 Hz), 7.47 (1.2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 3095, 1576, 1491, 1308, 1279, 1146, 1082, 879, 818, 800,752, 712, 621, 565, 474.

mp: 173-182° C.

MS m/z: 405 (M⁺+H).

Anal. Calcd for C₁₇H₁₅ClF₂O₃S₂: C, 50.43; H, 3.73; Cl, 8.76; F, 9.38; S,15.85. Found: C, 50.60; H, 3.76; Cl, 8.81; F, 9.48; S, 15.92.

Example 2534-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)tetrahydrothiopyran-1,1-dioxide

The4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)tetrahydrothiopyran(100 mg, 0.254 mmol) obtained in Example 251 was dissolved indichloromethane (15 ml), followed by the addition of 3-chloroperbenzoicacid (110 mg, 0.637 mmol) under ice cooling. After stirring at roomtemperature for 5 hours, diethyl ether was added. The resulting mixturewas washed with a 1N aqueous solution of sodium hydroxide, and theorganic layer was dried over anhydrous magnesium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel chromatography,and the fraction obtained from the hexane:ethyl acetate=1:1 eluate wasconcentrated under reduced pressure to give a white solid. The whitesolid was washed with diethyl ether, whereby the title compound (89 mg,0.211 mmol, 83%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.80-3.02 (4H, m), 3.02-3.24 (4H, m),6.91-7.01 (1H, m), 7.06-7.13 (1H, m), 7.14-7.22 (1H, m), 7.39 (2H, d,J=8.7 Hz), 7.44 (2H, d, J=8.7 Hz).

IR (ATR) cm⁻¹: 1577, 1496, 1473, 1415, 1311, 1201, 1149, 1122, 1080,874, 854, 822, 754, 708, 623, 567, 474.

mp: 204-206° C.

MS m/z: 421 (M⁺+H).

Anal. Calcd for C₁₇H₁₅ClF₂O₄S₂: C, 48.51; H, 3.59; Cl, 8.42; F, 9.03; S,15.24. Found: C, 48.61; H, 3.60; Cl, 8.44; F, 9.05; S, 15.21.

Example 2542-[3-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propylsulfinyl]ethanol

The2-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propylthio]ethanol(65 mg, 0.16 mmol) obtained in Example 250 was dissolved indichloromethane (5 ml), followed by the addition of 3-chloroperbenzoicacid (33 mg, 0.19 mmol) under ice cooling. The resulting mixture wasstirred at room temperature for 14 hours. The residue obtained byconcentrating the reaction mixture under reduced pressure was subjectedto flash silica gel chromatography, and the fraction obtained from thedichloromethane:methanol=30:1 eluate was concentrated under reducedpressure to give a white solid. The white solid was washed with diethylether, whereby the title compound (50 mg, 0.12 mmol, 74%) was obtainedas a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.52-2.65 (2H, m), 2.80-3.02 (5H, m),4.11-4.22 (2H, m), 4.68-4.78 (1H, m), 6.80-6.90 (1H, m), 6.97-7.04 (1H,m), 7.21-7.30 (1H, m), 7.38-7.44 (2H, m), 7.50-7.58 (2H, m).

IR (ATR) cm⁻¹: 3421, 3259, 1585, 1496, 1319, 1147, 1086, 1028, 989, 833,756, 555, 534, 480, 463.

mp: 124-132° C.

MS m/z: 423 (M⁺+H).

Anal. Calcd for C₁₇H₁₇ClF₂O₄S₂: C, 48.28; H, 4.05; Cl, 8.42; F, 9.03; S,15.24. Found: C, 48.03; H, 4.01; Cl, 8.33; F, 8.93; S, 15.06.

Example 2552-[3-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propylsulfonyl]ethanol

The2-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propylthio]ethanol(65 mg, 0.16 mmol) obtained in Example 250 was dissolved indichloromethane (5 ml), followed by the addition of 3-chloroperbenzoicacid (66 mg, 0.38 mmol) under ice cooling. At room temperature, themixture was stirred for 14 hours. The residue obtained by concentratingthe reaction mixture under reduced pressure was subjected to flashsilica gel chromatography, and the fraction obtained from thehexane:ethyl acetate=1:1 eluate was concentrated under reduced pressureto give a white solid. The white solid was washed with diethyl ether,whereby the title compound (53 mg, 0.12 mmol, 76%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.19 (1H, t, J=5.1 Hz), 2.56-2.70 (1H, m),2.97-3.10 (1H, m), 3.12-3.28 (4H, m), 4.12 (2H, q, J=5.1 Hz), 4.77 (1H,dd, J=9.4, 5.7 Hz), 6.82-6.92 (1H, m), 6.98-7.07 (1H, m), 7.20-7.30 (1H,m), 7.41 (2H, d, J=8.7 Hz), 7.54 (2H, d, J=8.7 Hz).

IR (ATR) cm⁻¹: 3525, 3076, 1576, 1496, 1315, 1279, 1146, 1128, 1082,1034, 1011, 997, 835, 758, 631, 559, 542, 523, 488, 467, 430.

mp: 111-113° C.

MS m/z: 439 (M⁺+H).

Anal. Calcd for C₁₇H₁₇ClF₂O₅S₂: C, 46.52; H, 3.90; Cl, 8.08; F, 8.66; S,14.61. Found: C, 46.46; H, 3.82; Cl, 8.15; F, 8.66; S, 14.55.

Referential Example 42 t-ButylN-[2-(t-butyldiphenylsilyloxy)ethyl]-N-(2-hydroxyethyl)carbamate

In a dichloromethane/N,N-dimethylformamide (70 ml/70 ml) mixture weredissolved t-butyl N,N-bis(2-hydroxyethyl)carbamate (9.00 g, 43.8 mmol)and imidazole (2.60 g, 38.2 mmol), followed by the dropwise addition oft-butylchlorodiphenylsilane (8.1 ml, 31 mmol) at room temperature. Aftercompletion of the dropwise addition, the reaction mixture was stirred atroom temperature for 14 hours. The residue obtained by concentrating thereaction mixture under reduced pressure was added with diethyl ether.The resulting mixture was washed with water and the organic layer wasdried over anhydrous magnesium sulfate. After filtration, the filtratewas concentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography, and the fraction obtainedfrom the hexane:ethyl acetate=2:1 eluate was concentrated under reducedpressure, whereby the title compound (7.41 g, 16.7 mmol, 54%) wasobtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.05 (9H, s), 1.30-1.60 (9H, m), 3.30-3.52(4H, m), 3.68-3.90 (4H, m), 7.34-7.50 (6H, m), 7.60-7.72 (4H, m).

IR (ATR) cm⁻¹: 2931, 2858, 1693, 1670, 1408, 1365, 1171, 1144, 1105,1051, 933, 822, 737, 700, 613, 501.

MS m/z: 444 (M⁺+H).

Example 256 t-ButylN-[2-(t-Butyldiphenylsilyloxy)ethyl]-N-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]carbamate

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (500 mg, 1.65mmol) obtained in Example 5 and t-butylN-[2-(t-butyldiphenylsilyloxy)ethyl]-N-(2-hydroxyethyl)carbamate (950mg, 2.14 mmol) were dissolved in toluene (20 ml), followed by theaddition of cyanomethylenetri-n-butylphosphorane (600 mg, 2.49 mmol).Under an argon atmosphere, the resulting mixture was heated under refluxfor 9 hours. After the reaction mixture was allowed to cool down,t-butyl N-[2-(t-butyldiphenylsilyloxy)ethyl]-N-(2-hydroxyethyl)carbamate(500 mg, 1.13 mmol) and cyanomethylenetri-n-butylphosphorane (300 mg,1.24 mmol) were added thereto. Under an argon atmosphere, the resultingmixture was heated under reflux for 14 hours. After the reaction mixturewas allowed to cool down, the residue obtained by concentrating thereaction mixture under reduced pressure was subjected to flash silicagel chromatography, and the fraction obtained from the hexane:ethylacetate=15:1 eluate was concentrated under reduced pressure, whereby thetitle compound (1.14 g, 1.57 mmol, 95%) was obtained as a pale yellowishbrown foam.

¹H-NMR (400 MHz, CDCl₃) δ: 0.97 (9H, s), 1.20-1.50 (9H, m), 2.29 (1H, brs), 2.62-2.78 (1H, m), 3.05-3.50 (4H, m), 3.66 (2H, br s), 4.40-4.60(1H, m), 6.81 (1H, br s), 6.98 (1H, br s), 7.18-7.70 (15H, m).

IR (ATR) cm⁻¹: 2931, 1689, 1585, 1496, 1473, 1323, 1149, 1086, 737, 700,613, 467, 426.

MS m/z: 726 (M⁺+H).

Example 257 t-ButylN-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]-N-(2-hydroxyethyl)carbamate

In tetrahydrofuran (20 ml) was dissolved t-butylN-[2-(t-butyldiphenylsilyloxy)ethyl]-N-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]carbamate(1.13 g, 1.55 mmol). Under ice cooling, a tetrahydrofuran solution(1.0M, 5.0 ml, 5.0 mmol) of tetrabutylammonium fluoride was addeddropwise. The resulting mixture was stirred at room temperature for 1hour. Water (2 ml) was added to the reaction mixture. The residueobtained by concentrating the resulting mixture under reduced pressurewas subjected to flash silica gel chromatography, and the fractionobtained from the hexane:ethyl acetate=1:1 eluate was concentrated underreduced pressure, whereby the title compound (651 mg, 1.32 mmol, 85%)was obtained as a white foam.

¹H-NMR (400 MHz, CDCl₃) δ: 1.39 (9H, s), 2.28-2.42 (1H, m), 2.70-2.80(1H, m), 3.15-3.32 (3H, m), 3.40 (1H, br s), 3.68-3.80 (2H, m), 4.54(1H, br s), 6.78-6.88 (1H, m), 6.95-7.03 (1H, m), 7.20-7.31 (1H, m),7.39 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz).

IR (ATR) cm⁻¹: 3438, 2976, 2933, 1685, 1583, 1496, 1475, 1319, 1279,1147, 1084, 1012, 827, 756, 710, 629, 555, 525, 467.

MS m/z: 490 (M⁺+H), 512 (M⁺+Na).

Anal. Calcd for C₂₂H₂₆ClF₂NO₅S.0.25H₂O: C, 53.44; H, 5.40; Cl, 7.17; F,7.68; N, 2.83; S, 6.48. Found: C, 53.39; H, 5.45; Cl, 7.21; F, 7.48; N,2.95; S, 6.51.

Example 2582-[3-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propylamino]ethanolhydrochloride

In dichloromethane (5 ml) was dissolved t-butylN-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]-N(2-hydroxyethyl)carbamate (300 mg, 0.607 mmol) and trifluoroacetic acid(0.5 ml) was added dropwise to the resulting solution under ice cooling.After stirring at room temperature for 2 hours, the reaction mixture wasconcentrated under reduced pressure. To the residue was added a 1Nsolution (5 ml) of hydrochloric acid in ethanol, followed byconcentration under reduced pressure to give a white solid. The solidthus obtained was washed with diethyl ether, whereby the title compound(249 mg, 0.579 mmol, 95%) was obtained as a white powder.

¹H-NMR (400 MHz, CD₃OD) δ: 2.42-2.58 (1H, m), 2.77-2.90 (1H, m), 2.96(1H, td, J=11.8, 4.8 Hz), 3.06-3.15 (2H, m), 3.22 (1H, td, J=11.8, 5.1Hz), 3.75 (2H, dd, J=5.7, 4.5 Hz), 4.89 (1H, dd, J=9.6, 5.3 Hz), 6.98(1H, td, J=9.3, 4.4 Hz), 7.10-7.20 (1H, m), 7.26-7.34 (1H, m), 7.54 (2H,d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 3535, 2956, 2902, 2677, 1576, 1496, 1306, 1232, 1192,1146, 1084, 1016, 822, 754, 710, 633, 548, 521, 472, 442.

mp: 216-220° C.

MS m/z: 390 (M⁺+H).

Anal. Calcd for C₁₇H₁₈ClF₂NO₃S.HCl.0.25H₂O: C, 47.40; H, 4.56; Cl,16.46; F, 8.82; N, 3.25; S, 7.44. Found: C, 47.52; H, 4.47; Cl, 16.47;F, 9.06; N, 3.36; S, 7.58.

Example 259 t-Butyl4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-1-piperidinecarboxylate

The t-butylN-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]-N-(2-hydroxyethyl)carbamate(200 mg, 0.404 mmol) obtained in Example 257 was dissolved in toluene(10 ml), followed by the addition ofcyanomethylenetri-n-butylphosphorane (200 mg, 0.829 mmol). Under anargon atmosphere, the resulting mixture was heated under reflux for 8hours. After the reaction mixture was allowed to cool down,cyanomethylenetri-n-butylphosphorane (200 mg, 0.829 mmol) was addedthereto. Under an argon atmosphere, the mixture was heated under refluxfor 14 hours. After the reaction mixture was allowed to cool down, theresidue obtained by concentrating the reaction mixture under reducedpressure was subjected to flash silica gel chromatography, and thefraction obtained from the hexane:ethyl acetate=4:1 eluate wasconcentrated under reduced pressure to give a white solid. The whitesolid was washed with diethyl ether, whereby the title compound (140 mg,0.297 mmol, 74%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.43 (9H, s), 2.27 (2H, br t, J=14.2 Hz),2.67 (4H, br s), 4.18 (2H, br s), 6.82-6.92 (1H, m), 7.03-7.16 (2H, m),7.36 (2H, d, J=8.7 Hz), 7.40 (2H, d, J=8.7 Hz).

IR (ATR) cm⁻¹: 2979, 1682, 1583, 1410, 1315, 1244, 1188, 1144, 1088,831, 754, 623, 563, 534, 474.

mp: 101-106° C.

MS m/z: 472 (M⁺+H).

Anal. Calcd for C₂₂H₂₄ClF₂NO₄S: C, 55.99; H, 5.13; Cl, 7.51; F, 8.05; N,2.97; S, 6.79. Found: C, 55.89; H, 5.19; Cl, 7.35; F, 7.97; N, 3.02; S,6.80.

Example 2604-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidinehydrochloride

In dichloromethane (100 ml) was dissolved t-butyl4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-1-piperidinecarboxylate(3.17 g, 6.72 mmol), followed by the dropwise addition oftrifluoroacetic acid (10.0 ml) under ice cooling. After stirring at roomtemperature for 2 hours, the reaction mixture was concentrated underreduced pressure. To the residue thus obtained was added a 1N solution(30 ml) of hydrochloric acid in ethanol. The resulting mixture wasconcentrated under reduced pressure to give a white solid. The whitesolid thus obtained was washed with diethyl ether, whereby the titlecompound (2.74 g, 6.71 mmol, quant.) was obtained as a white powder.

¹H-NMR (400 MHz, CD₃OD) δ: 2.57 (2H, tm, J=14.1 Hz), 2.85 (2H, tm,J=12.6 Hz), 2.98 (2H, br s), 3.54 (2H, dm, J=13.7 Hz), 7.02-7.12 (1H,m), 7.22-7.31 (2H, m), 7.43 (2H, d, J=8.8 Hz), 7.55 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 3338, 2943, 2713, 1579, 1495, 1469, 1311, 1196, 1144,1082, 1012, 893, 818, 750, 623, 567.

mp: 239-246° C. (decomp.).

MS m/z: 372 (M⁺+H).

Anal. Calcd for C₁₇H₁₆ClF₂NO₂S.HCl.0.75H₂O: C, 48.41; H, 4.42; Cl,16.81; F, 9.01; N, 3.32; S, 7.60. Found: C, 48.60; H, 4.31; Cl, 16.33;F, 9.16; N, 3.46; S, 7.80.

Example 2614-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-1-methylpiperidine

To dichloromethane (5 ml) were added4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidinehydrochloride (100 mg, 0.245 mmol), triethylamine (0.070 ml, 0.50 mmol)and a 37% aqueous formaldehyde solution (0.060 ml, 0.739 mmol), followedby the addition of sodium triacetoxyborohydride (220 mg, 1.04 mmol) atroom temperature. After stirring at room temperature for 14 hours, a 1Naqueous sodium hydroxide solution (6.0 ml) was added. The mixture wasstirred at room temperature for 30 minutes. To the reaction mixture wasadded diethyl ether and the mixture was washed with a 1N aqueous sodiumhydroxide solution. The organic layer was dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure. The residue thus obtained was subjected to flash silica gelchromatography, and the fraction obtained from thedichloromethane:methanol=30:1 eluate was concentrated under reducedpressure to give a white solid. The solid thus obtained was washed withdiisopropyl ether, whereby the title compound (70 mg, 0.18 mmol, 74%)was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.90 (2H, tm, J=12.5 Hz), 2.17 (3H, s), 2.42(2H, tm, J=11.8 Hz), 2.50-2.90 (2H, m), 2.89 (2H, dt, J=12.0, 2.9 Hz),6.82-6.92 (1H, m), 7.03-7.16 (2H, m), 7.38 (2H, d, J=9.0 Hz), 7.42 (2H,d, J=9.0 Hz).

IR (ATR) cm⁻¹: 3084, 3006, 2943, 2850, 2796, 1577, 1496, 1462, 1313,1281, 1184, 1147, 1086, 814, 752, 712, 631, 571, 534, 474, 440.

mp: 172-175° C.

MS m/z: 386 (M⁺+H).

Anal. Calcd for C₁₈H₁₈ClF₂NO₂S: C, 56.03; H, 4.70; Cl, 9.19; F, 9.85; N,3.63; S, 8.31. Found: C, 55.92; H, 4.72; Cl, 9.10; F, 9.91; N, 3.67; S,8.39.

Example 2621-Benzyl-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidine

The 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidinehydrochloride (100 mg, 0.245 mmol) obtained in Example 260,triethylamine (0.070 ml, 0.50 mmol) and benzaldehyde (0.050 ml, 0.428mmol) were added to dichloromethane (5 ml), followed by the addition ofsodium triacetoxyborohydride (110 mg, 0.500 mmol) at room temperature.The resulting mixture was stirred at room temperature for 14 hours. A 1Naqueous sodium hydroxide solution (3.0 ml) was then added. The resultingmixture was stirred at room temperature for 30 minutes. After diethylether was added, the resulting mixture was washed with a 1N aqueoussodium hydroxide solution. The organic layer was dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel chromatography, and the fraction obtained from thedichloromethane:methanol=50:1 eluate was concentrated under reducedpressure, whereby the title compound (87 mg, 0.19 mmol, 77%) wasobtained as a white foam.

¹H-NMR (400 MHz, CDCl₃) δ: 1.93 (2H, br t, J=12.5 Hz), 2.46 (2H, br t,J=11.6 Hz), 2.65 (2H, br s), 2.93 (2H, dm, J=12.5 Hz), 3.36 (2H, s),6.81-6.94 (1H, m), 7.00-7.15 (2H, m), 7.20-7.34 (5H, m), 7.37 (4H, s).

IR (ATR) cm⁻¹: 2812, 2769, 1583, 1495, 1313, 1259, 1188, 1144, 1088,810, 752, 698, 629, 571, 542, 469.

MS m/z: 462 (M⁺+H).

Anal. Calcd for C₂₄H₂₂ClF₂NO₂S: C, 62.40; H, 4.80; Cl, 7.67; F, 8.23; N,3.03; S, 6.94. Found: C, 62.50; H, 4.98; Cl, 7.50; F, 8.05; N, 3.04; S,6.90.

Example 2631-[4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidino]-1-ethanone

The 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidinehydrochloride (90 mg, 0.22 mmol) obtained in Example 260 andtriethylamine (0.092 ml, 0.66 mmol) were dissolved in dichloromethane (4ml), followed by the addition of acetyl chloride (0.024 ml, 0.34 mmol)at room temperature. After stirring at room temperature for 14 hours, asaturated aqueous solution of sodium bicarbonate (0.5 ml) was added. Theresidue obtained by concentrating the resulting mixture under reducedpressure was subjected to flash silica gel chromatography, and thefraction obtained from the dichloromethane:methanol=30:1 eluate wasconcentrated under reduced pressure to give a white solid. The solidthus obtained was washed with hexane, whereby the title compound (48 mg,0.12 mmol, 53%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.08 (3H, s), 2.20-2.42 (2H, m), 2.49 (1H, brt, J=13.0 Hz), 2.60-2.75 (1H, m), 2.75-2.90 (1H, m), 3.01 (1H, br t,J=13.2 Hz), 3.92 (1H, dm, J=13.4 Hz), 4.70 (1H, dm, J=13.9 Hz),6.85-6.94 (1H, m), 7.50-7.60 (2H, m), 7.36 (2H, d, J=8.8 Hz), 7.40 (2H,d, J=8.8 Hz).

IR (ATR) cm⁻¹: 3084, 1653, 1496, 1427, 1309, 1279, 1244, 1144, 1088,993, 754, 627, 563, 474.

mp: 159-160° C.

MS m/z: 414 (M⁺+H).

Anal. Calcd for C₁₉H₁₈ClF₂NO₃S: C, 55.14; H, 4.38; Cl, 8.57; F, 9.18; N,3.38; S, 7.75. Found: C, 55.07; H, 4.49; Cl, 8.69; F, 9.30; N, 3.41; S,7.77.

Example 264[4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidino](4-pyridyl)methanone

In a similar manner to Example 263 except for the use of the4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidinehydrochloride (80 mg, 0.20 mmol) obtained in Example 260 andisonicotinoyl chloride hydrochloride (60 mg, 0.34 mmol), the titlecompound (84 mg, 0.18 mmol, 90%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.24-2.55 (2H, m), 2.60-2.90 (3H, m),2.90-3.10 (1H, m), 3.70-3.82 (1H, m), 4.74-4.90 (1H, m), 6.84-6.92 (1H,m), 7.04-7.14 (2H, m), 7.18-7.25 (2H, m), 7.34 (2H, d, J=8.5 Hz), 7.39(2H, d, J=8.5 Hz), 8.70 (2H, d, J=5.9 Hz).

IR (ATR) cm⁻¹: 3032, 1630, 1496, 1439, 1311, 1279, 1146, 1086, 1013,810, 752, 625, 561, 505.

mp: 245-248° C.

MS m/z: 477 (M⁺+H).

FAB-MS: 477.0839 (Calcd for C₂₃H₂₀ClF₂N₂O₃S: 477.0851).

Example 265[4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidino](3-pyridyl)methanone

In a similar manner to Example 263 except for the use of the4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidinehydrochloride (90 mg, 0.22 mmol) obtained in Example 260 and niconitonylchloride hydrochloride (60 mg, 0.34 mmol), the title compound (75 mg,0.16 mmol, 71%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.20-4.90 (8H, m), 6.85-6.95 (1H, m),7.08-7.18 (2H, m), 7.32-7.43 (1H, m), 7.35 (2H, d, J=8.9 Hz), 7.40 (2H,d, J=8.9 Hz), 7.73 (1H, dt, J=7.8, 2.0 Hz), 8.62 (1H, dd, J=2.0, 1.0Hz), 8.68 (1H, dd, J=4.9, 2.0 Hz). IR (ATR) cm⁻¹: 1631, 1585, 1493,1444, 1315, 1144, 1088, 831, 756, 625, 557, 505, 474.

mp: 119-124° C.

MS m/z: 477 (M⁺+H)

Anal. Calcd for C₂₃H₁₉ClF₂N₂O₃S: C, 57.92; H, 4.02; Cl, 7.43; F, 7.97;N, 5.87; S, 6.72. Found: C, 57.69; H, 4.08; Cl, 7.33; F, 7.97; N, 5.94;S, 6.78.

Example 266[4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidino](2-pyridyl)methanone

In a similar manner to Example 263 except for the use of4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidinehydrochloride (80 mg, 0.20 mmol) obtained in Example 260 and picolinoylchloride hydrochloride (60 mg, 0.34 mmol), the title compound (77 mg,0.16 mmol, 82%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.35-2.52 (2H, m), 2.60-2.90 (3H, m), 3.09(1H, br t, J=13.1 Hz), 4.21 (1H, dm, J=13.5 Hz), 4.83 (1H, dm, J=14.0Hz), 6.82-6.95 (1H, m), 7.04-7.18 (2H, m), 7.30-7.45 (5H, m), 7.65 (1H,dm, J=7.8 Hz), 7.80 (1H, td, J=7.8, 1.7 Hz), 8.55 (1H, dm, J=4.9 Hz).

IR (ATR) cm⁻¹: 3084, 1635, 1496, 1311, 1146, 1086, 1007, 843, 804, 752,629, 555, 467.

mp: 193-196° C.

MS m/z: 477 (M⁺+H).

Anal. Calcd for C₂₃H₁₉ClF₂N₂O₃S: C, 57.92; H, 4.02; Cl, 7.43; F, 7.97;N, 5.87; S, 6.72. Found: C, 57.94; H, 4.08; Cl, 7.48; F, 7.99; N, 5.92;S, 6.81.

Example 267 Methyl4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-1-piperidinecarboxylate

In a similar manner to Example 263 except for the use of4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidinehydrochloride (90 mg, 0.22 mmol) obtained in Example 260 and methylchloroformate (0.026 ml, 0.34 mmol), the title compound (62 mg, 0.14mmol, 65%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.29 (2H, tm, J=12.1 Hz), 2.55-2.85 (4H, m),3.68 (3H, s), 4.22 (2H, br s), 6.82-6.92 (1H, m), 7.05-7.15 (2H, m),7.36 (2H, d, J=8.8 Hz), 7.40 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 1695, 1493, 1450, 1400, 1248, 1188, 1142, 1090, 901, 825,623, 565, 534, 474.

mp: 123-126° C.

MS m/z: 430 (M⁺+H).

Anal. Calcd for C₁₉H₁₈ClF₂NO₄S: C, 53.09; H, 4.22; Cl, 8.25; F, 8.84; N,3.26; S, 7.46. Found: C, 52.89; H, 4.20; Cl, 8.27; F, 8.90; N, 3.35; S,7.58.

Example 268N,N-dimethyl-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-1-piperidinecarboxamide

In a similar manner to Example 263 except for the use of4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidinehydrochloride (90 mg, 0.22 mmol) obtained in Example 260 andN,N-dimethylcarbamoyl chloride (0.031 ml, 0.34 mmol), the title compound(81 mg, 0.18 mmol, 83%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.40 (2H, br t, J=12.1 Hz), 2.60-2.80 (4H,m), 2.81 (6H, s), 3.72 (2H, dm, J=13.7 Hz), 6.82-6.92 (1H, m), 7.04-7.14(2H, m), 7.35 (2H, d, J=9.0 Hz), 7.39 (2H, d, J=9.0 Hz).

IR (ATR) cm⁻¹: 1651, 1576, 1496, 1469, 1365, 1308, 1190, 1146, 1074,1034, 914, 814, 758, 752, 617, 561, 474.

mp: 143-146° C.

MS m/z: 443 (M⁺+H).

Anal. Calcd for C₂₀H₂₁ClF₂N₂O₃S: C, 54.24; H, 4.78; Cl, 8.00; F, 8.58;N, 6.32; S, 7.24. Found: C, 53.96; H, 4.73; Cl, 8.14; F, 8.64; N, 6.34;S, 7.32.

Example 2694-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-1-(methylsulfonyl)piperidine

In a similar manner to Example 263 except for the use of the4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidinehydrochloride (90 mg, 0.22 mmol) obtained in Example 260 andmethanesulfonyl chloride (0.026 ml, 0.34 mmol), the title compound (72mg, 0.16 mmol, 73%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.48 (2H, br t, J=12.1 Hz), 2.60-2.90 (4H,m), 2.72 (3H, s), 3.88 (2H, dm, J=12.9 Hz), 6.88-6.96 (1H, m), 7.04-7.14(2H, m), 7.37 (2H, d, J=8.9 Hz), 7.42 (2H, d, J=8.9 Hz).

IR (ATR) cm⁻¹: 1579, 1495, 1308, 1257, 1138, 966, 814, 752, 623, 565,513.

mp: 176-178° C.

MS m/z: 450 (M⁺+H).

Anal. Calcd for C₁₈H₁₈ClF₂NO₃S: C, 48.05; H, 4.03; Cl, 7.88; F, 8.45; N,3.11; S, 14.25. Found: C, 48.02; H, 4.00; Cl, 7.91; F, 8.52; N, 3.22; S,14.28.

Example 270N,N-Dimethyl-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-1-piperidinesulfonamide

In a similar manner to Example 263 except for the use of the4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidinehydrochloride (90 mg, 0.22 mmol) obtained in Example 260 andN,N-dimethylsulfamoyl chloride (0.036 ml, 0.34 mmol), the title compound(84 mg, 0.18 mmol, 80%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.45 (2H, br t, J=12.5 Hz), 2.68-2.90 (4H,m), 2.79 (6H, s), 3.73 (2H, dm, J=13.4 Hz), 6.80-6.92 (1H, m), 7.05-7.14(2H, m), 7.34 (2H, d, J=8.8 Hz), 7.40 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 1576, 1493, 1469, 1315, 1144, 984, 904, 808, 742, 621,553, 519, 472.

mp: 125-129° C.

MS m/z: 479 (M⁺+H).

Anal. Calcd for C₁₉H₂₁ClF₂N₂O₄S₂: C, 47.65; H, 4.42; Cl, 7.40; F, 7.93;N, 5.85; S, 13.39. Found: C, 47.62; H, 4.40; Cl, 7.42; F, 8.03; N, 5.95;S, 13.43.

Example 2711-[4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidino]-2-(dimethylamino)-1-ethanone

The 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidinehydrochloride (100 mg, 0.245 mmol) obtained in Example 260,N,N-dimethylglycine (40 mg, 0.39 mmol) and N-methylmorpholine (0.142 ml,1.29 mmol) were dissolved in dichloromethane (5 ml), followed by theaddition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(80 mg, 0.42 mmol) at room temperature. After stirring at roomtemperature for 14 hours, a saturated aqueous solution (0.5 ml) ofsodium bicarbonate was added. The residue obtained by concentrating thereaction mixture under reduced pressure was subjected to flash silicagel chromatography, and the fraction obtained from thedichloromethane:methanol=30:1 eluate was concentrated under reducedpressure to give a white solid. The resulting solid was washed withdiisopropyl ether, whereby the title compound (70 mg, 0.15 mmol, 62%)was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.15-2.40 (2H, m), 2.25 (6H, s), 2.50 (1H, brt, J=12.9 Hz), 2.60-2.85 (2H, m), 2.93 (1H, br t, J=12.0 Hz), 3.03 (1H,d, J=13.2 Hz), 3.13 (1H, d, J=13.2 Hz), 4.32 (1H, br d, J=14.4 Hz), 4.67(1H, br d, J=13.7 Hz), 6.83-6.93 (1H, m), 7.02-7.16 (2H, m), 7.36 (2H,d, J=8.8 Hz), 7.40 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 2829, 2773, 1635, 1460, 1313, 1142, 1090, 827, 806, 754,625, 561, 523, 474.

mp: 88-92° C.

MS m/z: 457 (M⁺+H).

Anal. Calcd for C₂₁H₂₃ClF₂N₂O₃S: C, 55.20; H, 5.07; Cl, 7.76; F, 8.32;N, 6.13; S, 7.02. Found: C, 55.15; H, 5.18; Cl, 7.76; F, 8.40; N, 6.13;S, 7.13.

Example 272N-ethyl-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-1-piperidinecarboxamide

The 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidinehydrochloride (80 mg, 0.20 mmol) obtained in Example 260 andtriethylamine (0.092 ml, 0.66 mmol) were dissolved in dichloromethane (4ml), followed by the addition of ethyl isocyanate (0.027 ml, 0.34 mmol)at room temperature. After stirring at room temperature for 6 hours, asaturated aqueous solution of sodium bicarbonate (0.5 ml) was added. Theresidue obtained by concentrating the reaction mixture under reducedpressure was subjected to flash silica gel chromatography, and thefraction obtained from the dichloromethane:methanol=50:1 eluate wasconcentrated under reduced pressure to give a white solid. The resultingsolid was washed with diisopropyl ether, whereby the title compound (74mg, 0.17 mmol, 85%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.12 (3H, t, J=7.2 Hz), 2.33 (2H, br t,J=11.8 Hz), 2.72 (4H, br t, J=12.0 Hz), 3.18-3.30 (2H, m), 3.99 (2H, dm,J=13.4 Hz), 4.30-4.40 (1H, m), 6.84-6.95 (1H, m), 7.05-7.15 (2H, m),7.37 (2H, d, J=8.8 Hz), 7.40 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 3286, 1622, 1496, 1309, 1265, 1144, 1090, 889, 825, 752,629, 567, 542, 474.

mp: 172-174° C.

MS m/z: 443 (M⁺+H).

Anal. Calcd for C₂₀H₂₁ClF₂N₂O₃S: C, 54.24; H, 4.78; Cl, 8.00; F, 8.58;N, 6.32; S, 7.24. Found: C, 54.18; H, 4.76; Cl, 8.15; F, 8.70; N, 6.41;S, 7.39.

Example 2732-[7-(t-Butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]heptyl]-1,4-difluorobenzene

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (470 mg, 1.55mmol) obtained in Example 5 and 6-(t-butyldiphenylsilyloxy)-1-hexanol(740 mg, 2.08 mmol) were dissolved in toluene (20 ml), followed by theaddition of cyanomethylenetri-n-butylphosphorane (500 mg, 2.07 mmol).Under an argon atmosphere, the resulting mixture was heated under refluxfor 7 hours. After the reaction mixture was allowed to cool down, theresidue obtained by concentrating the reaction mixture under reducedpressure was subjected to flash silica gel chromatography. The fractionobtained from the hexane:ethyl acetate=10:1 eluate was concentratedunder reduced pressure, whereby the title compound (786 mg, 1.23 mmol,79%) was obtained as a pale yellowish brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.02 (9H, s), 1.10-1.40 (6H, m), 1.42-1.55(2H, m), 2.00-2.14 (1H, m), 2.35-2.48 (1H, m), 3.60 (2H, t, J=6.5 Hz),4.49 (1H, dd, J=11.6, 2.6 Hz), 6.76-6.89 (1H, m), 6.94-7.03 (1H, m),7.20-7.30 (1H, m), 7.34-7.50 (8H, m), 7.53 (2H, d, J=8.6 Hz), 7.64 (4H,dm, J=8.1 Hz).

IR (ATR) cm⁻¹: 2931, 2856, 1583, 1496, 1427, 1323, 1149, 1105, 1084,822, 700, 627, 613, 503, 486, 467.

MS m/z: 641 (M⁺+H).

Example 2747-[(4-Chlorophenyl)sulfonyl]-7-(2,5-difluorophenyl)-1-heptanol

In tetrahydrofuran (20 ml) was dissolved2-[7-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]heptyl]-1,4-difluorobenzene(786 mg, 1.23 mmol), followed by the dropwise addition of atetrahydrofuran solution (1.0M, 4.0 ml, 4.0 mmol) of tetrabutylammoniumfluoride under ice cooling. The resulting mixture was stirred at roomtemperature for 14 hours. After addition of water (2 ml), the mixturewas concentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography, and the fraction obtainedfrom the hexane:ethyl acetate=2:1 eluate was concentrated under reducedpressure to give a white solid. The white solid was washed with hexane,whereby the title compound (403 mg, 1.00 mmol, 81%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.10-1.75 (9H, m), 2.02-2.20 (1H, m),2.38-2.52 (1H, m), 3.60 (2H, t, J=6.4 Hz), 4.50 (1H, dd, J=11.7, 3.2Hz), 6.78-6.90 (1H, m), 6.92-7.05 (1H, m), 7.20-7.35 (1H, m), 7.38 (2H,d, J=8.4 Hz), 7.53 (2H, d, J=8.4 Hz).

IR (ATR) cm⁻¹: 3338, 2935, 2860, 1583, 1495, 1325, 1149, 1082, 1012,752, 631, 542, 467.

mp: 77-79° C.

MS m/z: 403 (M⁺+H), 420 (M⁺+NH₄).

Anal. Calcd for C₁₉H₂₁ClF₂O₃S: C, 56.64; H, 5.25; Cl, 8.80; F, 9.43; S,7.96. Found: C, 56.16; H, 5.18; Cl, 8.80; F, 9.36; S, 8.00.

Example 2752-[1-[(4-Chlorophenyl)sulfonyl]cycloheptyl-1,4-difluorobenzene

In toluene (5 ml) was dissolved7-[(4-chlorophenyl)sulfonyl]-7-(2,5-difluorophenyl)-1-heptanol (200 mg,0.496 mmol), followed by the addition ofcyanomethylenetri-n-butylphosphorane (400 mg, 1.66 mmol). Under an argonatmosphere, the resulting mixture was heated under reflux for 14 hours.After the reaction mixture was allowed to cool down, the residueobtained by concentrating the reaction mixture under reduced pressurewas subjected to flash silica gel chromatography. The fraction obtainedfrom the hexane:ethyl acetate=10:1 eluate was concentrated under reducedpressure to give a white solid. The white solid was washed with hexane,whereby the title compound (111 mg, 0.288 mmol, 58%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.34-1.50 (4H, m), 1.50-1.68 (2H, m),1.82-1.98 (2H, m), 2.36 (2H, tm, J=12.5 Hz), 2.65-2.78 (2H, m),6.84-6.94 (1H, m), 6.97-7.08 (2H, m), 7.34 (2H, d, J=9.0 Hz), 7.37 (2H,d, J=9.0 Hz).

IR (ATR) cm⁻¹: 2931, 2856, 1577, 1493, 1473, 1308, 1277, 1186, 1140,1086, 1012, 881, 818, 748, 710, 615, 559, 467.

mp: 101-103° C.

MS m/z: 402 (M⁺+NH₄).

Anal. Calcd for C₁₉H₁₉ClF₂O₂S: C, 59.29; H, 4.98; Cl, 9.21; F, 9.87; S,8.33. Found: C, 59.21; H, 4.86; Cl, 9.25; F, 9.96; S, 8.48.

Example 2762-[2-[2-[(t-Butyldiphenylsilyloxy)methyl]phenyl]-1-[(4-chlorophenyl)sulfonyl]ethyl]-1,4-difluorobenzene

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (600 mg, 1.98mmol) obtained in Example 5 and[2-[(t-butyldiphenylsilyloxy)methyl]phenyl]methanol (1.00 g, 2.66 mmol)were dissolved in toluene (20 ml), followed by the addition ofcyanomethylenetri-n-butylphosphorane (640 mg, 2.65 mmol). Under an argonatmosphere, the resulting mixture was heated under reflux for 14 hours.After the reaction mixture was allowed to cool down,2-[(t-butyldiphenylsilyloxy)methyl]phenyl]methanol (400 mg, 1.06 mmol)and cyanomethylenetri-n-butylphosphorane (400 mg, 1.66 mmol) were added.Under an argon atmosphere, the resulting mixture was heated under refluxfor 14 hours. After the reaction mixture was allowed to cool down, theresidue obtained by concentrating the mixture under reduced pressure wassubjected to flash silica gel chromatography. The fraction obtained fromthe hexane:ethyl acetate=15:1 eluate was concentrated under reducedpressure, whereby the title compound (1.13 g, 1.71 mmol, 86%) wasobtained as a pale yellowish brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.09 (9H, s), 3.30 (1H, dd, J=14.7, 11.2 Hz),3.80 (1H, dd, J=14.7, 3.4 Hz), 4.65 (1H, d, J=12.9 Hz), 4.70-4.85 (2H,m), 6.64-6.74 (1H, m), 6.82 (1H, d, J=6.8 Hz), 6.85-6.94 (1H, m), 7.03(1H, td, J=7.5, 1.4 Hz), 7.15 (1H, td, J=7.5, 1.2 Hz), 7.20-7.55 (12H,m), 7.65-7.76 (4H, m).

IR (ATR) cm⁻¹: 2931, 2856, 1583, 1496, 1473, 1427, 1319, 1149, 1111,1082, 822, 740, 700, 634, 501.

MS m/z: 661 (M⁺+H), 683 (M⁺+Na).

Example 277[2-[2-[(4-Chlorophenyl)sulfonyl]-2-(2,5-difluorophenyl)ethyl]phenyl]methanol

In tetrahydrofuran (20 ml) was dissolved2-[2-[2-[(t-butyldiphenylsilyloxy)methyl]phenyl]-1-[(4-chlorophenyl)sulfonyl]ethyl]-1,4-difluorobenzene(1.10 g, 1.66 mmol), followed by the dropwise addition of atetrahydrofuran solution (1.0M, 5.0 ml, 5.0 mmol) of tetrabutylammoniumfluoride under ice cooling. The resulting mixture was stirred at roomtemperature for 14 hours. After addition of water (3 ml), the residueobtained by concentrating the resulting mixture under reduced pressurewas subjected to flash silica gel chromatography. The fraction obtainedfrom the hexane:ethyl acetate=1:1 eluate was concentrated under reducedpressure to give a white solid. The white solid was washed withdiisopropyl ether, whereby the title compound (595 mg, 1.41 mmol, 85%)was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.92 (1H, dd, J=6.1, 4.9 Hz), 3.35 (1H, dd,J=14.1, 10.0 Hz), 4.00 (1H, dd, J=14.1, 3.4 Hz), 4.66 (1H, dd, J=12.3,4.9 Hz), 4.81 (1H, dd, J=12.3, 6.1 Hz), 5.10 (1H, dm, J=10.0 Hz),6.66-6.75 (1H, m), 6.82 (1H, d, J=7.5 Hz), 6.89-6.98 (1H, m), 7.06 (1H,td, J=7.5, 1.5 Hz), 7.17 (1H, td, J=7.5, 1.2 Hz), 7.29 (1H, dd, J=7.5,1.2 Hz), 7.38 (2H, d, J=8.7 Hz), 7.50 (1H, br s), 7.58 (2H, d, J=8.7Hz).

IR (ATR) cm⁻¹: 3506, 1576, 1493, 1313, 1279, 1213, 1144, 1080, 1014,829, 750, 708, 634, 536, 471.

mp: 107-108° C.

MS m/z: 422 (M⁺).

Anal. Calcd for C₂₁H₁₇ClF₂O₃S: C, 59.65; H, 4.05; Cl, 8.38; F, 8.99; S,7.58. Found: C, 59.46; H, 3.97; Cl, 8.41; F, 9.05; S, 7.67.

Example 278 2-[(4-Chlorophenyl)sulfonyl]-2-(2,5-difluorophenyl)indane

In toluene (5 ml) was dissolved2-[2-[(4-chlorophenyl)sulfonyl]-2-(2,5-difluorophenyl)ethyl]phenyl]methanol(80 mg, 0.19 mmol), followed by the addition ofcyanomethylenetri-n-butylphosphorane (140 mg, 0.580 mmol). Under anargon atmosphere, the resulting mixture was heated under reflux for 8hours. After the reaction mixture was allowed to cool down, the residueobtained by concentrating it under reduced pressure was subjected toflash silica gel chromatography, and the fraction obtained from thehexane:ethyl acetate=5:1 eluate was concentrated under reduced pressureto give a white solid. The white solid was washed with diisopropylether, whereby the title compound (32 mg, 0.079 mmol, 42%) was obtainedas a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 3.72 (2H, dm, J=17.6 Hz), 4.18 (2H, dd,J=17.6, 2.9 Hz), 6.95-7.04 (1H, m), 7.04-7.12 (4H, m), 7.12-7.21 (1H,m), 7.21-7.30 (1H, m), 7.23 (2H, d, J=8.7 Hz), 7.45 (2H, d, J=8.7 Hz).

IR (ATR) cm⁻¹: 1572, 1495, 1306, 1138, 1078, 821, 754, 656, 598, 571,525, 478, 451.

mp: 209-210° C. (dec.).

MS m/z: 422 (M⁺+NH₄).

Example 2792-[1-[(4-Chlorophenyl)sulfonyl]-2-methylcyclopentyl]-1,4-difluorobenzene

The2-[5-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-2-methylpentyl]-1,4-difluorobenzene(isomer mixture) (1.40 g, 2.23 mmol) obtained in Example 38 wasdissolved in tetrahydrofuran (30 ml), followed by the addition of atetrahydrofuran solution (1.0M, 5.0 ml, 5.0 mmol) of tetrabutylammoniumfluoride under ice cooling. The resulting mixture was stirred at roomtemperature for 14 hours. After addition of water (3 ml), the residueobtained by concentrating the resulting mixture under reduced pressurewas subjected to flash silica gel chromatography. The fraction obtainedfrom the hexane:ethyl acetate=2:1 eluate was concentrated under reducedpressure, whereby5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-4-methyl-1-pentanol(isomer mixture) (879 mg, quant.) was obtained as a colorless oil.

The resulting5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-4-methyl-1-pentanol(isomer mixture) was dissolved in toluene (10 ml), followed by theaddition of cyanomethylenetri-n-butylphosphorane (1.00 g, 4.14 mmol).Under an argon atmosphere, the resulting mixture was heated under refluxfor 14 hours. After the reaction mixture was allowed to cool down, theresidue obtained by concentrating the reaction mixture under reducedpressure was subjected to flash silica gel chromatography. The fractionobtained from the hexane:ethyl acetate=20:1 eluate was concentratedunder reduced pressure to give a white solid. The white solid was washedwith hexane, whereby the title compound (423 mg, 1.14 mmol, 51%) wasobtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 0.85 (1H, d, J=6.8 Hz), 1.50-1.80 (1.67H, m),1.72 (2H, d, J=7.1 Hz), 1.84-2.50 (3H, m), 2.62-3.05 (2H, m), 3.30-3.45(0.33H, m), 6.72-6.92 (1.33H, m), 6.92-7.06 (1H, m), 7.12-7.22 (0.67H,m), 7.27-7.40 (4H, m).

IR (ATR) cm⁻¹: 1579, 1493, 1300, 1263, 1190, 1136, 1092, 1080, 1012,839, 823, 756, 746, 712, 638, 600, 579, 546, 517, 472.

mp: 105-109° C.

MS m/z: 393 (M⁺+Na).

Anal. Calcd for C₁₈H₁₇ClF₂O₂S: C, 58.30; H, 4.57; Cl, 9.71; F, 10.15; S,8.79. Found: C, 58.27; H, 4.57; Cl, 9.71; F, 10.15; S, 8.79.

Referential Example 43 (2-Bromomethylbenzyloxy)-t-butyldiphenylsilane

In dichloromethane (50 ml) were dissolved[2-[(t-butyldiphenylsilyloxy)methyl]phenyl]methanol (3.00 g, 7.97 mmol)and carbon tetrabromide (3.40 g, 10.3 mmol). Under ice cooling, adichloromethane solution (5 ml) of triphenylphosphine (2.70 g, 10.3mmol) was added dropwise. After stirring at room temperature for 14hours, the reaction mixture was concentrated under reduced pressure. Theresidue thus obtained was subjected to silica gel chromatography. Thefraction obtained from the hexane:ethyl acetate=30:1 eluate wasconcentrated under reduced pressure, whereby the title compound (3.12 g,7.10 mmol, 89%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.05 (9H, s), 4.51 (2H, s), 4.88 (2H, s),7.20-7.51 (10H, m), 7.68 (4H, dd, J=7.6, 1.2 Hz).

IR (ATR) cm⁻¹: 2929, 2856, 1427, 1105, 1068, 822, 739, 698, 607, 501.

Example 280 t-Butyl[[2-[[(4-chlorophenyl)sulfonyl]methyl]benzyl]oxy]diphenylsilane

In propanol (20 ml) was dissolved (2-bromomethylbenzyloxy)-t-butyldiphenylsilane (3.10 g, 7.05 mmol), followed bythe addition of sodium 4-chlorobenzenesulfinate (1.80 g, 9.06 mmol). At90° C., the resulting mixture was stirred for 14 hours. After thereaction mixture was allowed to cool down, the residue obtained byconcentrating the reaction mixture under reduced pressure was added withethyl acetate. The resulting mixture was washed with water, and theorganic layer was dried over anhydrous magnesium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure,whereby the title compound (3.90 g, quant.) was obtained as a whitesolid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.03 (9H, s), 4.43 (2H, s), 4.47 (2H, s),7.20-7.28 (1H, m), 7.28-7.37 (4H, m), 7.37-7.52 (9H, m), 7.60 (4H, dd,J=7.8, 1.5 Hz).

MS m/z: 535 (M⁺+H).

Example 281 t-Butyl[[2-[1-[(4-chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzyl]oxy]diphenylsilane

In toluene (5 ml) were dissolved t-butyl[[2-[[(4-chlorophenyl)sulfonyl]methyl]benzyl]oxy]diphenylsilane (350 mg,0.654 mmol) and the 4-(methylsulfonyl)-1-butanol (200 mg, 1.31 mmol)obtained in Referential Example 3, followed by the addition ofcyanomethylenetri-n-butylphosphorane (350 mg, 1.45 mmol). Under an argonatmosphere, the resulting mixture was heated under reflux for 14 hours.After the reaction mixture was allowed to cool down,cyanomethylenetri-n-butylphosphorane (300 mg, 1.24 mmol) was addedthereto. Under an argon atmosphere, the resulting mixture was heatedunder reflux for 14 hours. The reaction mixture was then allowed to cooldown. The residue obtained by concentrating the mixture under reducedpressure was subjected to flash silica gel chromatography, and thefraction obtained from the hexane:ethyl acetate=3:2 was concentratedunder reduced pressure, whereby the title compound (175 mg, 0.261 mmol,40%) was obtained as a pale yellowish brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.05 (9H, s), 1.18-1.30 (1H, m), 1.30-1.44(1H, m), 1.70-1.84 (2H, m), 2.08-2.24 (1H, m), 2.35-2.48 (1H, m),2.74-2.85 (2H, m), 2.80 (3H, s), 4.13 (1H, d, J=12.7 Hz), 4.35 (1H, d,J=12.7 Hz), 4.51 (1H, dd, J=10.8, 4.4 Hz), 7.18-7.25 (3H, m), 7.25-7.45(8H, m), 7.45-7.53 (3H, m), 7.55-7.68 (4H, m).

IR (ATR) cm⁻¹: 2929, 2856, 1583, 1473, 1321, 1147, 1105, 1088, 833, 775,741, 702, 623, 569, 503.

MS m/z: 669 (M⁺+H), 691 (M⁺+Na).

Example 282[2-[1-[(4-Chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]phenyl]methanol

In tetrahydrofuran (5 ml) was dissolved t-butyl[[2-[1-[(4-chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzyl]oxy]diphenylsilane(175 mg, 0.261 mmol). Under ice cooling, a tetrahydrofuran solution(1.0M, 0.6 ml, 0.6 mmol) of tetrabutylammonium fluoride was addeddropwise to the resulting solution. The resulting mixture was thenstirred at room temperature for 1 hour. After addition of water (0.5ml), the residue obtained by concentrating the resulting mixture underreduced pressure was subjected to flash silica gel chromatography. Thefraction obtained from the dichloromethane:methanol=30:1 eluate wasconcentrated under reduced pressure, whereby the title compound (87 mg,0.20 mmol, 61%) was obtained as a pale yellowish brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.20-1.60 (2H, m), 1.65-1.95 (2H, m),2.10-2.40 (3H, m), 2.70-3.00 (2H, m), 2.82 (3H, s), 4.43 (2H, d, J=4.9Hz), 4.81 (1H, dd, J=11.1, 4.0 Hz), 7.15-7.30 (1H, m), 7.30-7.50 (5H,m), 7.56 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 3506, 2931, 1579, 1475, 1394, 1277, 1138, 1084, 1012,964, 829, 798, 756, 712, 629, 563, 519, 463.

MS m/z: 448 (M⁺+NH₄), 453 (M⁺+Na).

Example 283 t-Butyl[[6-[2-[(t-butyldiphenylsilyloxy)methyl]phenyl]-6-[(4-chlorophenyl)sulfonyl]hexyl]oxy]dimethylsilane

The t-butyl[[2-[[(4-chlorophenyl)sulfonyl]methyl]benzyl]oxy]diphenylsilane (1.00 g,1.87 mmol) obtained in Example 280 and5-(t-butyldiphenylsilyloxy)-1-pentanol (0.68 ml, 2.8 mmol) weredissolved in toluene (7 ml), followed by the addition ofcyanomethylenetri-n-butylphosphorane (650 mg, 2.69 mmol). Under an argonatmosphere, the resulting mixture was heated under reflux for 14 hours.After the reaction mixture was allowed to cool down,5-(t-butyldiphenylsilyloxy)-1-pentanol (0.34 ml, 1.4 mmol) andcyanomethylenetri-n-butylphosphorane (300 mg, 1.24 mmol) were added.Under an argon atmosphere, the resulting mixture was heated under refluxfor 10 hours. The reaction mixture was then allowed to cool down. Theresidue obtained by concentrating the mixture under reduced pressure wassubjected to flash silica gel chromatography, and the fraction obtainedfrom the hexane:ethyl acetate=15:1 eluate was concentrated under reducedpressure, whereby the title compound (932 mg, 1.27 mmol, 68%) wasobtained as a pale yellowish brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.00 (6H, s), 0.80-1.60 (6H, m), 0.86 (9H,s), 1.04 (9H, s), 2.04-2.20 (1H, m), 2.28-2.40 (1H, m), 3.48 (2H, t,J=6.3 Hz), 4.10 (1H, d, J=12.9 Hz), 4.35-4.48 (2H, m), 7.16-7.23 (2H,m), 7.23-7.55 (12H, m), 7.55-7.70 (4H, m).

IR (ATR) cm⁻¹: 2929, 2856, 1583, 1473, 1321, 1147, 1103, 1088, 1014,831, 775, 741, 700, 623, 567, 503.

MS m/z: 735 (M⁺+H), 757 (M⁺+Na).

Example 2846-[2-(t-Butyldiphenylsilyloxy)methylphenyl]-6-[(4-chlorophenyl)sulfonyl]-1-hexanol

In methanol (30 ml) was dissolved t-butyl[[6-[2-[(t-butyldiphenylsilyloxy)methyl]phenyl]-6-[(4-chlorophenyl)sulfonyl]hexyl]oxy]dimethylsilane(830 mg, 1.13 mmol), followed by the addition of p-toluenesulfonic acidmonohydrate (25 mg, 0.13 mmol). The resulting mixture was stirred atroom temperature for 2 hours. Triethylamine (0.080 ml, 0.57 mmol) wasadded and then, the residue obtained by concentrating the resultingmixture under reduced pressure was subjected to flash silica gelchromatography. The fraction obtained from thedichloromethane:methanol=100:1 eluate was concentrated under reducedpressure, whereby the title compound (580 mg, 0.934 mmol, 83%) wasobtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.04 (9H, s), 1.10-1.50 (7H, m), 2.08-2.20(1H, m), 2.30-2.42 (1H, m), 3.45-3.56 (2H, m), 4.11 (1H, d, J=12.7 Hz),4.40 (1H, d, J=12.7 Hz), 4.44 (1H, dd, J=11.0, 4.2 Hz), 7.15-7.22 (2H,m), 7.22-7.36 (5H, m), 7.36-7.51 (7H, m), 7.58 (2H, dd, J=8.1, 1.5 Hz),7.63 (2H, dd, J=8.1, 1.5 Hz).

MS m/z: 621 (M⁺+H), 638 (M⁺+Na).

Example 285 6-[(4-Chlorophenyl)sulfonyl]-6-(2-hydroxymethylphenyl)-1-hexanol

In tetrahydrofuran (5 ml) was dissolved6-[2-(t-butyldiphenylsilyloxy)methylphenyl]-6-[(4-chlorophenyl)sulfonyl]-1-hexanol(200 mg, 0.322 mmol), followed by the dropwise addition of atetrahydrofuran solution (1.0M, 0.7 ml, 0.7 mmol) of tetrabutylammoniumfluoride under ice cooling. The resulting mixture was stirred at roomtemperature for 1 hour. Water (0.2 ml) was then added. The residueobtained by concentrating the resulting mixture under reduced pressurewas subjected to flash silica gel chromatography. The fraction obtainedfrom the dichloromethane:methanol=30:1 eluate was concentrated underreduced pressure, whereby the title compound (86 mg, 0.23 mmol, 70%) wasobtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.10-1.60 (7H, m), 2.08-2.30 (2H, m), 2.37(1H, br s), 3.45-3.60 (2H, m), 4.44-4.60 (2H, m), 4.78 (1H, dd, J=11.0,4.2 Hz), 7.28-7.50 (4H, m), 7.43 (2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8Hz).

IR (ATR) cm⁻¹: 3367, 2935, 2862, 1579, 1475, 1392, 1308, 1277, 1142,1082, 1012, 756, 631, 565, 461.

MS m/z: 735 (M⁺+H), 757 (M⁺+Na).

FAB-MS: 383.1098 (Calcd for C₁₉H₂₄ClO₄S: 383.1084).

Example 286 [2-[1-[(4-Chlorophenyl)sulfonyl]cyclohexyl]phenyl]methanol

The6-[2-(t-butyldiphenylsilyloxy)methylphenyl]-6-[(4-chlorophenyl)sulfonyl]-1-hexanol(447 mg, 0.719 mmol) obtained in Example 284 was dissolved in toluene (5ml), followed by the addition of cyanomethylenetri-n-butylphosphorane(350 mg, 0.1.45 mmol). Under an argon atmosphere, the resulting mixturewas heated under reflux for 14 hours. The reaction mixture was thenallowed to cool down. The residue obtained by concentrating the mixtureunder reduced pressure was subjected to flash silica gel chromatography.The fraction obtained from the hexane:ethyl acetate=15:1 eluate wasconcentrated under reduced pressure to yield a colorless oil (190 mg).

The resulting colorless oil was dissolved in tetrahydrofuran (5 ml).Under ice cooling, a tetrahydrofuran solution (11.0M, 0.6 ml, 0.6 mmol)of tetrabutylammonium fluoride was added dropwise. At room temperature,the resulting mixture was stirred for 2 hours. Water (1.0 ml) was thenadded to the reaction mixture. The residue obtained by concentrating thereaction mixture under reduced pressure was subjected to flash silicagel chromatography. The fraction obtained from the hexane:ethylacetate=4:1 eluate was concentrated under reduced pressure to give awhite solid. The white solid was washed with hexane, whereby the titlecompound (40 mg, 0.11 mmol, 15%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.15-1.45 (3H, m), 1.45-1.80 (2H, m),1.80-1.98 (1H, m), 2.00-2.25 (2H, m), 2.40-2.60 (1H, m), 3.05-3.25 (2H,m), 4.70-4.90 (1H, m), 5.03-5.20 (1H, m), 6.85 (1H, dm, J=7.6 Hz), 7.09(1H, tm, J=7.7 Hz), 7.24-7.40 (5H, m), 7.62 (1H, dd, J=7.7, 1.6 Hz).

IR (ATR) cm⁻¹: 3575, 2925, 1574, 1471, 1448, 1389, 1296, 1275, 1136,1082, 1011, 989, 835, 785, 706, 615, 577, 467.

mp: 148-150° C. (dec.).

MS m/z: 382 (M⁺+NH₄).

Anal. Calcd for C₁₉H₂₁ClO₃S: C, 62.54; H, 5.80; Cl, 9.72; S, 8.79.Found: C, 62.54; H, 5.73; Cl, 9.70; S, 8.93.

Example 2874-[[(4-Chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]tetrahydropyran

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg,0.661 mmol) obtained in Example 5 and tetrahydro-4H-pyran-4-ol (0.13 ml,1.36 mmol) were dissolved in toluene (10 ml), followed by the additionof cyanomethylenetri-n-butylphosphorane (330 mg, 1.37 mmol). Under anargon atmosphere, the resulting mixture was heated under reflux for 14hours. After the reaction mixture was allowed to cool down,cyanomethylenetri-n-butylphosphorane (200 mg, 0.829 mmol) was addedthereto. Under an argon atmosphere, the mixture was heated under refluxfor 14 hours. The reaction mixture was then allowed to cool down. Theresidue obtained by concentrating the mixture under reduced pressure wassubjected to flash silica gel chromatography. The fraction obtained fromthe hexane:ethyl acetate=4:1 eluate was concentrated under reducedpressure to give a white solid. The white solid was washed with hexane,whereby the title compound (157 mg, 0.406 mmol, 61%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.28-1.48 (2H, m), 1.71 (1H, ddd, J=25.3,11.7, 4.3 Hz), 2.37 (1H, br d, J=12.7 Hz), 2.70-2.88 (1H, m), 3.40 (1H,td, J=11.7, 2.5 Hz), 3.50 (1H, td, J=12.0, 2.2 Hz), 3.91 (1H, dm, J=11.2Hz), 4.02 (1H, dm, J=11.7 Hz), 4.46 (1H, d, J=8.8 Hz), 6.68-6.80 (1H,m), 6.88-6.98 (1H, m), 7.31 (2H, d, J=8.5 Hz), 7.36-7.45 (1H, m), 7.49(2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 2952, 2833, 1576, 1495, 1308, 1275, 1236, 1144, 1082,879, 829, 788, 752, 733, 710, 615, 602, 559, 519, 465, 447.

mp: 150-152° C.

MS m/z: 387 (M⁺+H)

Anal. Calcd for C₁₈H₁₇ClF₂O₃S: C, 55.89; H, 4.43; Cl, 9.16; F, 9.82; S,8.29. Found: C, 55.64; H, 4.27; Cl, 9.41; F, 9.89; S, 8.28.

Referential Example 44 Tetrahydrothiopyran-4-ol

Tetrahydrothiopyran-4-one (5.00 g, 43.0 mmol) was dissolved in methanol(100 ml). Under ice cooling, sodium borohydride (1.6 g, 42.3 mmol) wasadded and the resulting mixture was stirred at room temperature for 14hours. The residue obtained by concentrating the reaction mixture underreduced pressure was added with water (50 ml). The resulting mixture wasmade weakly acidic with 1N hydrochloric acid, and then it was extractedwith diethyl ether. The extract was washed successively with 1Nhydrochloric acid, a saturated aqueous solution of sodium bicarbonate,and brine. The organic layer was dried over anhydrous magnesium sulfate.After filtration, the filtrate was concentrated under reduced pressure,whereby the title compound (4.40 g, 37.2 mmol, 87%) was obtained as apale yellowish brown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.47 (1H, br s), 1.64-1.80 (2H, m), 2.10-2.24(2H, m), 2.55-2.70 (2H, m), 2.73-2.88 (2H, m), 3.60-3.75 (1H, m).

MS m/z: 119 (M⁺+H).

Example 2884-[[(4-Chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]tetrahydrothiopyran

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (500 mg, 1.65mmol) obtained in Example 5 and tetrahydrothiopyran-4-ol (400 mg, 3.38mmol) were dissolved in toluene (20 ml), followed by the addition ofcyanomethylenetri-n-butylphosphorane (800 mg, 3.31 mmol). Under an argonatmosphere, the resulting mixture was heated under reflux for 14 hours.After the reaction mixture was allowed to cool down,cyanomethylenetri-n-butylphosphorane (400 mg, 1.66 mmol) was added.Under an argon atmosphere, the resulting mixture was heated under refluxfor 14 hours. The reaction mixture was then allowed to cool down. Theresidue obtained by concentrating the reaction mixture under reducedpressure was subjected to flash silica gel chromatography, and thefraction obtained from the hexane:ethyl acetate=15:1 eluate wasconcentrated under reduced pressure to give a white solid. The whitesolid was washed with a hexane/diisopropyl ether mixture, whereby thetitle compound (404 mg, 1.00 mmol, 61%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.47 (1H, ddd, J=23.4, 10.0, 3.3 Hz), 1.68(1H, ddd, J=25.0, 11.4, 3.3 Hz), 2.13 (1H, dm, J=11.4 Hz), 2.50-2.78(5H, m), 2.82 (1H, td, J=12.8, 2.6 Hz), 4.47 (1H, d, J=7.3 Hz),6.72-6.82 (1H, m), 6.90-7.00 (1H, m), 7.31 (2H, d, J=8.8 Hz), 7.40-7.60(1H, m), 7.49 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 2939, 2887, 1576, 1493, 1425, 1317, 1281, 1240, 1142,1084, 1012, 866, 831, 781, 750, 731, 710, 631, 615, 548, 467.

mp: 150-152° C.

MS m/z: 403 (M⁺+H).

Anal. Calcd for C₁₈H₁₇ClF₂O₂S₂: C, 53.66; H, 4.25; Cl, 8.80; F, 9.43; S,15.92. Found: C, 53.52; H, 4.21; Cl, 9.00; F, 9.54; S, 15.88.

Example 2894-[[(4-Chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]tetrahydrothiopyran-1,1-dioxide(Compound A) and4-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]tetrahydrothiopyran-1-oxide(Compound B (Isomer A) and Compound B (Isomer B))

Compound A Compound B

In dichloromethane (15 ml) was dissolved4-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]tetrahydrothiopyran(360 mg, 0.893 mmol). Under ice cooling, 3-chloroperbenzoic acid (320mg, 1.85 mmol) was added to the solution. The resulting mixture wasstirred at room temperature for 14 hours. The residue obtained byconcentrating the reaction mixture under reduced pressure was subjectedto flash silica gel chromatography, and the fraction obtained from thehexane:ethyl acetate=1:1 eluate was concentrated under reduced pressureto give a white solid. The white solid was dissolved in dichloromethane.The resulting solution was washed successively with a 1N aqueoussolution of sodium hydroxide and brine. The organic layer was dried overanhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure to give a white solid. The whitesolid was washed with diethyl ether, whereby the title compound A (187mg, 0.430 mmol, 48%) was obtained as a white powder. The fractionobtained from the dichloromethane:methanol=50:1 eluate was concentratedunder reduced pressure, whereby a mixture of the title compound B(Isomer A) and the title compound B (Isomer B) was obtained as a whitesolid. The resulting mixture was separated and purified by flash silicagel chromatography (dichloromethane:methanol=80:1). The white solidswere each washed with diethyl ether, whereby obtained were the titlecompound B (Isomer A) (low polarity) (78 mg, 0.19 mmol, 21%) and thetitle compound B (Isomer B) (high polarity) (69 mg, 0.17 mmol, 19%),each as a white powder.

Compound A

¹H-NMR (400 MHz, CDCl₃) δ: 1.85-2.00 (1H, m), 2.18-2.35 (2H, m),2.68-2.91 (2H, m), 2.98-3.10 (2H, m), 3.10-3.28 (2H, m), 4.54 (1H, br d,J=7.1 Hz), 6.74-6.90 (1H, m), 6.94-7.06 (1H, m), 7.33 (2H, d, J=8.7 Hz),7.35-7.55 (1H, m), 7.49 (2H, d, J=8.7 Hz).

IR (ATR) cm⁻¹: 1576, 1493, 1290, 1146, 1120, 1080, 874, 829, 752, 735,710, 631, 623, 592, 552, 530, 498, 471, 424.

mp: 245-248° C.

MS m/z: 435 (M⁺+H).

Anal. Calcd for C₁₈H₁₇ClF₂O₄S₂: C, 49.71; H, 3.94; Cl, 8.15; F, 8.74; S,14.75. Found: C, 49.38; H, 3.87; Cl, 8.50; F, 8.86; S, 14.62.

Compound B (Isomer A)

¹H-NMR (400 MHz, CDCl₃) δ: 1.76 (1H, br d, J=13.4 Hz), 2.18 (1H, ddm,J=25.4, 12.5 Hz), 2.32-2.70 (4H, m), 2.74-2.90 (1H, m), 2.98 (1H, dm,J=14.0 Hz), 3.09 (1H, dm, J=14.4 Hz), 4.53 (1H, d, J=7.3 Hz), 6.72-6.86(1H, m), 6.90-7.02 (1H, m), 7.32 (2H, d, J=8.5 Hz), 7.40-7.60 (1H, m),7.49 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 1585, 1495, 1315, 1300, 1242, 1220, 1147, 1086, 1049,997, 874, 831, 752, 733, 625, 596, 553, 525, 482.

mp: 255-256° C.

MS m/z: 419 (M⁺+H).

Anal. Calcd for C₁₈H₁₇ClF₂O₃S₂: C, 51.61; H, 4.09; Cl, 8.46; F, 9.07; S,15.31. Found: C, 51.51; H, 4.04; Cl, 8.69; F, 9.15; S, 15.20.

Compound B (Isomer B)

¹H-NMR (400 MHz, CDCl₃) δ: 1.42 (1H, ddm, J=22.3, 11.7 Hz), 1.92 (1H,ddm, J=11.7, 11.0 Hz), 2.14-2.27 (1H, m), 2.66 (1H, td, J=12.2, 2.7 Hz),2.70-2.90 (3H, m), 3.10-3.24 (1H, m), 3.32-3.44 (1H, m), 4.49 (1H, d,J=8.1 Hz), 6.72-6.85 (1H, m), 6.90-7.02 (1H, m), 7.32 (2H, d, J=8.5 Hz),7.34-7.50 (1H, m), 7.48 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 2912, 1574, 1496, 1298, 1246, 1144, 1080, 1001, 800, 752,735, 714, 619, 561, 552, 517, 469.

mp: 184-187° C.

MS m/z: 419 (M⁺+H).

Anal. Calcd for C₁₈H₁₇ClF₂O₃S₂: C, 51.61; H, 4.09; Cl, 8.46; F, 9.07; S,15.31. Found: C, 51.82; H, 4.23; Cl, 8.42; F, 9.12; S, 15.07.

Example 290 t-Butyl4-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-1-piperidinecarboxylate

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (1.25 g, 4.13mmol) obtained in Example 5 and t-butyl4-hydroxy-1-piperidinecarboxylate (1.70 g, 8.44 mmol) were dissolved intoluene (50 ml), followed by the addition ofcyanomethylenetri-n-butylphosphorane (2.00 g, 8.29 mmol). Under an argonatmosphere, the resulting mixture was heated under reflux for 14 hours.The reaction mixture was allowed to cool down. The residue obtained byconcentrating the reaction mixture under reduced pressure was subjectedto flash silica gel chromatography. The fraction obtained from thehexane:ethyl acetate=1:1 eluate was concentrated under reduced pressureto give a white solid. The white solid was washed with diethyl ether,whereby the title compound (1.68 g, 3.46 mmol, 84%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.10-1.25 (1H, m), 1.40-1.70 (2H, m), 1.44(9H, s), 2.30-2.50 (1H, m), 2.60-2.95 (3H, m), 4.00-4.25 (2H, m), 4.45(1H, d, J=7.8 Hz), 6.69-6.80 (1H, m), 6.88-6.98 (1H, m), 7.31 (2H, d,J=8.6 Hz), 7.35-7.50 (1H, m), 7.49 (2H, d, J=8.6 Hz). IR (ATR) cm⁻¹:2979, 2935, 1682, 1583, 1493, 1421, 1319, 1281, 1240, 1165, 1122, 1078,881, 835, 793, 752, 634, 534, 472.

mp: 193-196° C.

MS m/z: 486 (M⁺+H), 508 (M⁺+Na).

Anal. Calcd for C₂₃H₂₆ClF₂NO₄S: C, 56.84; H, 5.39; Cl, 7.30; F, 7.82; N,2.88; S, 6.60. Found: C, 56.41; H, 5.43; Cl, 7.77; F, 7.61; N, 2.99; S,6.58.

Example 2914-[[(4-Chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]piperidinehydrochloride

In dichloromethane (50 ml) was dissolved t-butyl4-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-1-piperidinecarboxylate(1.56 g, 3.21 mmol). Under ice cooling, trifluoroacetic acid (5.0 ml)was added dropwise to the resulting solution. After stirring at roomtemperature for 2 hours, the reaction mixture was concentrated underreduced pressure. Dichloromethane (10 ml) and a 1N ethanol solution (10ml) of hydrochloric acid were added, followed by concentration underreduced pressure to give a white solid. The resulting solid was washedwith diethyl ether, whereby the title compound (1.36 g, 3.12 mmol, 97%)was obtained as a white powder.

¹H-NMR (400 MHz, CD₃OD) δ: 1.38-1.52 (1H, m), 1.70-1.92 (2H, m), 2.73(1H, br d, J=14.2 Hz), 2.86-3.00 (1H, m), 3.05 (1H, td, J=12.9, 3.1 Hz),3.13 (1H, td, J=13.1, 3.1 Hz), 3.30-3.40 (1H, m), 3.48 (1H, dm, J=13.0Hz), 4.72 (1H, d, J==8.6 Hz), 6.82-6.98 (1H, m), 7.04-7.12 (1H, m),7.40-7.55 (1H, m), 7.44 (2H, d, J=8.6 Hz), 7.57 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 2950, 2719, 1583, 1491, 1317, 1146, 1084, 831, 752, 617,596, 552, 470.

mp: 184-190° C.

MS m/z: 386 (M⁺+H).

Anal. Calcd for C₁₈H₁₈ClF₂NO₂S.HCl.0.75H₂O: C, 49.61; H, 4.74; Cl,16.27; F, 8.72; N, 3.21; S, 7.36. Found: C, 49.57; H, 4.75; Cl, 15.79;F, 9.16; N, 3.34; S, 7.25.

Example 2922-[1-[(4-Chlorophenyl)sulfonyl]-2-methylpentyl]-1,4-difluorobenzene(Isomer 292-A and Isomer 292-B)

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg,0.661 mmol) obtained in Example 5 and 2-pentanol (0.144 ml, 1.33 mmol)were dissolved in toluene (3 ml), followed by the addition ofcyanomethylenetri-n-butylphosphorane (0.320 ml). Under an argonatmosphere, the resulting mixture was heated under reflux for 14 hours.The reaction mixture was then allowed to cool down. The residue obtainedby concentrating the reaction mixture under reduced pressure wasseparated and purified by flash silica gel chromatography (hexane:ethylacetate=50:1), whereby obtained were the title Isomer 292-A (lowpolarity) (67 mg, 0.18 mmol, 27%) as a white powder and the title Isomer292-B (high polarity) (45 mg, 0.12 mmol, 19%) as a white solid.

Isomer 292-A

¹H-NMR (400 MHz, CDCl₃) δ: 0.91 (3H, t, J=7.1 Hz), 1.08 (3H, d, J=6.9Hz), 1.20-1.52 (3H, m), 1.52-1.68 (1H, m), 2.72-2.90 (1H, m), 4.51 (1H,d, J=5.9 Hz), 6.73-6.85 (1H, m), 6.88-6.99 (1H, m), 7.32 (2H, d, J=8.6Hz), 7.46-7.60 (1H, m), 7.52 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 2970, 2866, 1583, 1496, 1475, 1394, 1303, 1277, 1234,1176, 1140, 1078, 1014, 883, 831, 790, 752, 727, 708, 621, 598, 561,534, 472.

mp: 85-87° C.

MS m/z: 373 (M⁺+H), 395 (M⁺+Na).

Anal. Calcd for C₁₈H₁₉ClF₂O₂S: C, 57.89; H, 5.14; Cl, 9.51; F, 10.19; S,8.61. Found: C, 57.96; H, 5.14; Cl, 9.44; F, 10.19; S, 8.75.

Isomer 292-B

¹H-NMR (400 MHz, CDCl₃) δ: 0.81 (3H, t, J=7.2 Hz), 1.00-1.12 (1H, m),1.15-1.45 (3H, m), 1.34 (3H, d, J=6.6 Hz), 2.60-2.72 (1H, m), 4.43 (1H,d, J=8.8 Hz), 6.67-6.78 (1H, m), 6.88-6.95 (1H, m), 7.29 (2H, d, J=8.6Hz), 7.36-7.45 (1H, m), 7.48 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 2976, 2933, 1585, 1495, 1394, 1323, 1238, 1178, 1149,1086, 1014, 868, 829, 783, 754, 729, 710, 625, 559, 528, 472.

mp: 47-50° C.

MS m/z: 373 (M⁺+H), 395 (M⁺+Na).

Anal. Calcd for C₁₈H₁₉ClF₂O₂S: C, 57.89; H, 5.14; Cl, 9.51; F, 10.19; S,8.61. Found: C, 57.97; H, 5.11; Cl, 9.45; F, 10.21; S, 8.69.

Example 2932-[1-[(4-Chlorophenyl)sulfonyl]-2-ethylpentyl]-1,4-difluorobenzene(Isomer 293-A and Isomer Mixture)

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg,0.661 mmol) obtained in Example 5 and 3-hexanol (0.150 ml, 1.35 mmol)were dissolved in toluene (3 ml), followed by the addition ofcyanomethylenetri-n-butylphosphorane (0.320 ml). Under an argonatmosphere, the resulting mixture was heated under reflux for 14 hours.The reaction mixture was then allowed to cool down. The residue obtainedby concentrating the reaction mixture under reduced pressure wasseparated and purified by flash silica gel chromatography (hexane:ethylacetate=200:1), whereby obtained were the title Isomer 293-A (lowpolarity) (37 mg, 0.096 mmol, 15%) and the title Isomer mixture (44 mg,0.11 mmol, 17%), each as a white powder.

Isomer 293-A

¹H-NMR (400 MHz, CDCl₃) δ: 0.84 (3H, t, J=7.5 Hz), 0.95 (3H, t, J=7.3Hz), 1.00-1.16 (1H, m), 1.30-1.50 (2H, m), 1.55-1.90 (3H, m), 2.50-2.63(1H, m), 4.59 (1H, d, J=7.6 Hz), 6.69-6.80 (1H, m), 6.88-6.95 (1H, m),7.31 (2H, d, J=8.4 Hz), 7.40-7.50 (1H, m), 7.50 (2H, d, J=8.4 Hz). IR(ATR) cm⁻¹: 2966, 1583, 1496, 1475, 1306, 1277, 1242, 1176, 1140, 1086,881, 831, 802, 752, 725, 710, 621, 561, 538, 478, 462, 451.

mp: 85-89° C.

MS m/z: 387 (M⁺+H), 409 (M⁺+Na).

Anal. Calcd for C₁₉H₂₁ClF₂O₂S: C, 58.98; H, 5.47; Cl, 9.16; F, 9.82; S,8.29. Found: C, 59.18; H, 5.65; Cl, 9.16; F, 9.83; S, 8.38.

Isomer Mixture

¹H-NMR (400 MHz, CDCl₃) δ: 0.84 (3H, t, J=7.5 Hz), 0.90-1.00 (3H, m),1.00-1.16 (1H, m), 1.20-1.50 (2H, m), 1.55-1.90 (3H, m), 2.50-2.63 (1H,m), 4.55-4.65 (1H, m), 6.69-6.80 (1H, m), 6.88-6.95 (1H, m), 7.31 (2H,d, J=8.4 Hz), 7.40-7.50 (1H, m), 7.50 (2H, d, J=8.4 Hz).

IR (ATR) cm⁻¹: 2956, 1583, 1572, 1495, 1479, 1319, 1298, 1279, 1230,1142, 1090, 1016, 887, 812, 752, 715, 660, 615, 563, 534, 469.

mp: 95-99° C.

MS m/z: 387 (M⁺+H), 409 (M⁺+Na).

Anal. Calcd for C₁₉H₂₁ClF₂O₂S: C, 58.98; H, 5.47; Cl, 9.16; F, 9.82; S,8.29. Found: C, 58.99; H, 5.37; Cl, 9.19; F, 9.88; S, 8.43.

Example 2942-[2-[(4-Chlorophenyl)sulfonyl]-2-(2,5-difluorophenyl)ethyl]tetrahydrofuran(Isomer 294-A and Isomer 294-B)

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg,0.661 mmol) obtained in Example 5 and tetrahydrofurfuryl alcohol (0.13ml, 1.34 mmol) were dissolved in toluene (3 ml), followed by theaddition of cyanomethylenetri-n-butylphosphorane (0.320 ml). Under anargon atmosphere, the resulting mixture was heated under reflux for 14hours. The reaction mixture was then allowed to cool down. The residueobtained by concentrating the reaction mixture under reduced pressurewas separated and purified by flash silica gel chromatography (using ahexane/ethyl acetate mixed solvent) to give a white solid. The whitesolid was washed with hexane, whereby obtained were the title Isomer294-A (low polarity) (102 mg, 0.264 mmol, 40%) and the title Isomer294-B (high polarity) (39 mg, 0.10 mmol, 15%), each as a white powder.

Isomer 294-A

¹H-NMR (400 MHz, CDCl₃) δ: 1.50-1.65 (1H, m), 1.75-2.05 (3H, m), 2.26(1H, tm, J=12.9 Hz), 2.48 (1H, tm, J=10.4 Hz), 3.50-3.60 (1H, m),3.60-3.70 (1H, m), 3.76-3.88 (1H, m), 4.86 (1H, dm, J=12.2 Hz),6.78-6.90 (1H, m), 6.92-7.01 (1H, m), 7.20-7.30 (1H, m), 7.38 (2H, d,J=8.6 Hz), 7.54 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 2960, 2852, 1576, 1493, 1309, 1281, 1194, 1132, 1084,1065, 1012, 903, 831, 810, 775, 746, 727, 708, 596, 575, 536, 471, 436.

mp: 99-105° C.

MS m/z: 387 (M⁺+H).

Anal. Calcd for C₁₈H₁₇ClF₂O₃S: C, 55.89; H, 4.43; Cl, 9.16; F, 9.82; S,8.29. Found: C, 56.28; H, 4.80; Cl, 8.94; F, 9.63; S, 8.19.

Isomer 294-B

¹H-NMR (400 MHz, CDCl₃) δ: 1.42-1.58 (1H, m), 1.76-1.04 (3H, m),2.22-2.33 (1H, m), 2.58-2.70 (1H, m), 3.60-3.70 (1H, m), 3.70-3.80 (1H,m), 3.88-3.99 (1H, m), 4.64-4.73 (1H, m), 6.75-6.88 (1H, m), 6.92-7.01(1H, m), 7.20-7.30 (1H, m), 7.38 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7Hz).

IR (ATR) cm⁻¹: 2976, 1585, 1496, 1311, 1277, 1221, 1153, 1088, 1061,922, 879, 829, 779, 752, 712, 629, 607, 561, 532, 472.

mp: 98-105° C.

MS m/z: 387 (M⁺+H).

Anal. Calcd for C₁₈H₁₇ClF₂O₃S: C, 55.89; H, 4.43; Cl, 9.16; F, 9.82; S,8.29. Found: C, 55.88; H, 4.54; Cl, 9.22; F, 9.96; S, 8.42.

Example 2952-[2-[(4-Chlorophenyl)sulfonyl]-2-(2,5-difluorophenyl)ethyl]thiophene

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg,0.330 mmol) obtained in Example 5 and 2-thiophenemethanol (0.065 ml,0.69 mmol) were dissolved in toluene (3 ml), followed by the addition ofcyanomethylenetri-n-butylphosphorane (0.160 ml). Under an argonatmosphere, the resulting mixture was heated under reflux for 14 hours.The reaction mixture was then allowed to cool down. The residue obtainedby concentrating the reaction mixture under reduced pressure waspurified by flash silica gel chromatography (using a hexane/ethylacetate solvent mixture) to give a white solid. The resulting whitesolid was washed with hexane, whereby the title compound (92 mg, 0.23mmol, 70%) was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 3.60 (1H, dd, J=15.1, 11.9 Hz), 4.02 (1H, dm,J=15.1 Hz), 4.80 (1H, dd, J=11.9, 2.5 Hz), 6.69 (1H, dd, J=3.5, 1.1 Hz),6.70-6.84 (2H, m), 6.92-7.00 (1H, m), 7.04 (1H, dd, J=5.3, 1.1 Hz),7.32-7.44 (1H, m), 7.39 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 1496, 1319, 1244, 1219, 1149, 1084, 1014, 881, 825, 775,758, 694, 629, 532, 467.

mp: 127-130° C.

MS m/z: 399 (M⁺+H).

Anal. Calcd for C₁₈H₁₃ClF₂O₂S₂: C, 54.20; H, 3.29; Cl, 8.89; F, 9.53; S,16.08. Found: C, 54.19; H, 3.31; Cl, 9.20; F, 9.51; S, 16.24.

Example 2962-[2-[(4-Chlorophenyl)sulfonyl]-2-(2,5-difluorophenyl)ethyl]furan

In a similar manner to Example 295 except for the use of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330mmol) obtained in Example 5 and furfuryl alcohol (0.060 ml, 0.69 mmol),the title compound (26 mg, 0.068 mmol, 21%) was obtained as a whitepowder.

¹H-NMR (400 MHz, CDCl₃) δ: 3.43 (1H, dd, J=15.4, 11.6 Hz), 3.78 (1H, dd,J=15.4, 3.7 Hz), 4.93 (1H, dd, J=11.6, 3.7 Hz), 5.89-5.91 (1H, m), 6.14(1H, dd, J=3.2, 1.7 Hz), 6.73-6.82 (1H, m), 6.90-6.99 (1H, m), 7.19 (1H,dd, J=1.7, 0.7 Hz), 7.25-7.34 (1H, m), 7.40 (2H, d, J=8.8 Hz), 7.58 (2H,d, J=8.8 Hz).

IR (ATR) cm⁻¹: 1585, 1495, 1319, 1151, 1086, 1014, 926, 831, 762, 613,594, 573, 552, 532, 472.

mp: 90-93° C.

MS m/z: 383 (M⁺+H).

Anal. Calcd for C₁₈H₁₃ClF₂O₃S: C, 56.48; H, 3.42; Cl, 9.26; F, 9.93; S,8.38. Found: C, 56.53; H, 3.39; Cl, 9.17; F, 9.92; S, 8.55.

Example 2971-[3-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]-1H-pyrrole

In a similar manner to Example 295 except for the use of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330mmol) obtained in Example 5 and 1-(2-hydroxyethyl)pyrrole (0.070 ml,0.67 mmol), the title compound (46 mg, 0.12 mmol, 35%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.42-2.57 (1H, m), 2.88-3.00 (1H, m), 3.79(1H, ddd, J=14.3, 8.5, 5.9 Hz), 4.06 (1H, dtm, J=14.3, 7.1 Hz), 4.34(1H, dd, J=10.0, 3.9 Hz), 6.11 (2H, t, J=2.2 Hz), 6.49 (2H, t, J=2.2Hz), 6.80-6.88 (1H, m), 6.98-7.06 (1H, m), 7.18-7.24 (1H, m), 7.36 (2H,d, J=8.8 Hz), 7.47 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 1576, 1493, 1325, 1306, 1271, 1236, 1176, 1146, 1082,877, 827, 764, 737, 714, 677, 621, 588, 553, 519, 463, 428.

mp: 108-113° C.

MS m/z: 396 (M⁺+H).

Anal. Calcd for C₁₉H₁₆ClF₂NO₂S: C, 57.65; H, 4.07; Cl, 8.96; F, 9.60; N,3.54; S, 8.10. Found: C, 57.82; H, 4.05; Cl, 9.05; F, 9.69; N, 3.69; S,8.23.

Example 2984-[3-[(4-Chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]morpholine

In a similar manner to Example 295 except for the use of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330mmol) obtained in Example 5 and 4-(2-hydroxyethyl)morpholine (0.080 ml,0.66 mmol), the title compound (89 mg, 0.21 mmol, 65%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.08-2.28 (4H, m), 2.30-2.48 (3H, m),2.62-2.77 (1H, m), 3.61 (4H, t, J=4.6 Hz), 4.80 (1H, dm, J=9.8 Hz),6.78-6.87 (1H, m), 6.94-7.03 (1H, m), 7.21-7.30 (1H, m), 7.39 (2H, d,J=8.7 Hz), 7.54 (2H, d, J=8.7 Hz).

IR (ATR) cm⁻¹: 2827, 2792, 1585, 1495, 1477, 1313, 1279, 1238, 1151,1117, 1084, 1014, 868, 839, 752, 636, 559, 536, 468.

mp: 149-151° C.

MS m/z: 416 (M⁺+H).

FAB-MS: 416.0903 (Calcd for C₁₉H₂₁ClF₂O₃S: 416.0899).

Example 2992-[1-(4-Chlorophenylsulfonyl)-2-phenylpropyl]-1,4-difluorobenzene(Isomer 299-A and Isomer 299-B)

Under an argon atmosphere, the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330mmol) obtained in Example 5, and DL-1-phenylethyl alcohol (79.9 μl,0.661 mmol) were dissolved in toluene (3 ml), followed by the additionof cyanomethylenetri-n-butylphosphorane (159 μl, 0.661 mmol). Theresulting mixture was heated under reflux for 13 hours under an argonatmosphere. The reaction mixture was then concentrated. The residue thusobtained was separated and purified by flash chromatography on a silicagel column (hexane:ethyl acetate=85:15). The solids thus obtained wereeach washed with hexane, whereby obtained were the title Isomer 299-A(low-polarity compound) (53 mg, 0.130 mmol, 40%) as a white powder andthe title Isomer 299-B (high-polarity compound) (20 mg, 0.0492 mmol,15%) as colorless columnar crystals.

Isomer 299-A

¹H-NMR (400 MHz, CDCl₃) δ: 1.80 (3H, d, J=6.6 Hz), 3.83-3.94 (1H, m),4.81-4.92 (1H, m), 6.40-6.51 (1H, m), 6.63-6.72 (1H, m), 7.02-7.26 (6H,m), 7.28 (2H, d, J=8.6 Hz), 7.50 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 3087, 2931, 1575, 1492, 1452, 1427, 1394, 1315, 1282,1243, 1195, 1174, 1137, 1089, 1012.

mp: 160-161° C.

MS m/z: 407 (M⁺+H).

Anal. calcd for C₂₁H₁₇ClF₂O₂S: C, 61.99; H, 4.21; Cl, 8.71; F, 9.34; S,7.88. Found: C, 61.77; H, 4.23; Cl, 8.83; F, 9.24; S, 7.98.

Isomer 299-B

¹H-NMR (400 MHz, CDCl₃) δ: 1.25 (3H, d, J=7.1 Hz), 3.87 (1H, q, J=7.3Hz), 4.89 (1H, d, J=8.1 Hz), 6.89 (1H, td, J=8.9, 4.6 Hz), 6.99-7.05(1H, m), 7.11-7.23 (6H, m), 7.20 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8Hz).

IR (ATR) cm⁻¹: 3062, 2929, 1583, 1496, 1475, 1454, 1394, 1321, 1276,1243, 1176, 1143, 1085, 1012.

mp: 145-146° C.

MS m/z: 407 (M⁺+H).

FAB-MS: 407.0690 (Calcd for C₂₁H₁₈ClF₂O₂S: 407.0684).

Example 3002-[1-(4-Chlorophenylsulfonyl)-2-methyl-3-phenylpropyl]-1,4-difluorobenzene(Isomer 300-A and Isomer 300-B)

In a similar manner to Example 299 except for the use of2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.660mmol) obtained in Example 5, DL-1-phenyl-2-propanol (182 μl, 1.32 mmol),and cyanomethylenetri-n-butylphosphorane (318 μl, 1.32 mmol), the titleIsomer 300-A (low-polarity compound) (32 mg, 0.0760 mmol, 12%) and thetitle Isomer 300-B (high-polarity compound) (25 mg, 0.0594 mmol, 9%)were obtained, each as a white powder.

Isomer 300-A

¹H-NMR (400 MHz, CDCl₃) δ: 1.01 (3H, d, J=6.9 Hz), 2.46 (1H, dd, J=13.3,8.6 Hz), 2.10-3.13 (2H, m), 4.56 (1H, dd, J=8.9, 4.6 Hz), 6.82 (1H, td,J=8.9, 4.6 Hz), 6.94-6.99 (1H, m), 7.14-7.28 (6H, m), 7.32 (2H, d, J=8.6Hz), 7.50 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 3079, 2977, 1583, 1492, 1452, 1423, 1394, 1321, 1278,1232, 1172, 1147, 1085, 1012.

mp: 81-83° C.

MS m/z: 421 (M⁺+H).

Anal. calcd for C₂₂H₁₉ClF₂O₂S: C, 62.78; H, 4.55; Cl, 8.42; F, 9.03; S,7.62. Found: C, 62.72; H, 4.59; Cl, 8.53; F, 9.21; S, 7.82.

Isomer 300-B

¹H-NMR (400 MHz, CDCl₃) δ: 1.24 (3H, d, J=6.6 Hz), 2.22 (1H, dd, J=13.1,10.4 Hz), 2.90-2.98 (2H, m), 4.51 (1H, d, J=7.8 Hz), 6.77 (1H, td,J=9.1, 4.4 Hz), 6.92-6.97 (1H, m), 7.06-7.28 (6H, m), 7.32 (2H, d, J=8.6Hz), 7.52 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 2962, 1585, 1492, 1454, 1425, 1384, 1309, 1278, 1240,1143, 1093.

mp: 116-117° C.

MS m/z: 421 (M⁺+H).

Anal. calcd for C₂₂H₁₉ClF₂O₂S: C, 62.78; H, 4.55; Cl, 8.42; F, 9.03; S,7.62. Found: C, 62.74; H, 4.70; Cl, 8.55; F, 9.23; S, 7.77.

Example 3012-[1-(4-Chlorophenylsulfonyl)-3-phenylbutyl]-1,4-difluorobenzene (Isomer301-A and Isomer 301-B)

In a similar manner to Example 299 except for the use of2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.660mmol) obtained in Example 5, DL-2-phenyl-1-propanol (180 μl, 1.32 mmol),and cyanomethylenetri-n-butylphosphorane (318 μl, 1.32 mmol), the titleIsomer 301-A (low-polarity compound) (51 mg, 0.121 mmol, 18%) and thetitle Isomer 301-B (high-polarity compound) (84 mg, 0.200 mmol, 30%)were obtained, each as a white powder.

Isomer 301-A

¹H-NMR (400 MHz, CDCl₃) δ: 1.24 (3H, d, J=6.4 Hz), 2.31-2.40 (1H, m),2.62-2.73 (2H, m), 4.59-4.67 (1H, m), 6.74 (1H, td, J=9.1, 4.5 Hz),6.89-6.95 (1H, m), 7.06-7.25 (6H, m), 7.35 (2H, d, J=8.6 Hz), 7.48 (2H,d, J=8.6 Hz). IR (ATR) cm⁻¹: 3085, 2964, 1581, 1490, 1427, 1394, 1309,1276, 1228, 1174, 1143, 1083, 1010.

mp: 89-90° C.

MS m/z: 421 (M⁺+H).

Anal. calcd for C₂₂H₁₉ClF₂O₂S: C, 62.78; H, 4.55; Cl, 8.42; F, 9.03; S,7.62. Found: C, 62.56; H, 4.59; Cl, 8.53; F, 9.28; S, 7.80.

Isomer 301-B

¹H-NMR (400 MHz, CDCl₃) δ: 1.28 (3H, d, J=6.6 Hz), 2.37-2.64 (3H, m),4.13 (1H, d, J=12.0 Hz), 6.81 (1H, td, J=8.9, 4.4 Hz), 6.91 (2H, d,J=6.6 Hz), 6.97-7.03 (1H, m), 7.19-7.27 (4H, m), 7.32 (2H, d, J=8.6 Hz),7.41 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 3070, 2960, 1583, 1490, 1455, 1427, 1392, 1319, 1309,1276, 1224, 1143, 1087, 1012.

mp: 127-129° C.

MS m/z: 421 (M⁺+H).

Anal. calcd for C₂₂H₁₉ClF₂O₂S: C, 62.78; H, 4.55; Cl, 8.42; F, 9.03; S,7.62. Found: C, 62.52; H, 4.53; Cl, 8.51; F, 9.31; S, 7.81.

Example 3022-[1-(4-Chlorophenylsulfonyl)-2-methyl-4-phenylbutyl]-1,4-difluorobenzene(Isomer 302-A and Isomer 302-B)

In a similar manner to Example 299 except for the use ofDL-4-phenyl-2-butanol (101 μl, 0.661 mmol), the title

Isomer 302-A (low-polarity compound) (30 mg, 0.0690 mmol, 21%) and thetitle Isomer 302-B (high-polarity compound) (33 mg, 0.0759 mmol, 23%)were obtained, each as a white powder.

Isomer 302-A

¹H-NMR (400 MHz, CDCl₃) δ: 1.21 (3H, d, J=7.1 Hz), 1.38-1.58 (2H, m),1.99-2.09 (1H, m), 2.24-2.33 (1H, m), 2.61-2.71 (1H, m), 4.41 (1H, dd,J=11.5, 3.0 Hz), 6.83 (1H, td, J=9.1, 4.5 Hz), 6.94-7.00 (1H, m),7.03-7.28 (6H, m), 7.35 (2H, d, J=8.8 Hz), 7.47 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 2933, 2867, 1583, 1494, 1475, 1461, 1427, 1394, 1344,1315, 1278, 1228, 1141, 1085, 1012.

mp: 133-135° C.

MS m/z: 435 (M⁺+H).

FAB-MS: 435.1101 (Calcd for C₂₃H₂₂ClF₂O₂S: 435.0997).

Anal. calcd for C₂₃H₂₁ClF₂O₂S: C, 63.52; H, 4.87; Cl, 8.15; F, 8.74; S,7.37. Found: C, 63.98; H, 4.88; Cl, 8.14; F, 8.82; S, 7.58.

Isomer 302-B

¹H-NMR (400 MHz, CDCl₃) δ: 1.19 (3H, d, J=6.8 Hz), 1.38-1.59 (2H, m),1.83-1.93 (1H, m), 2.26-2.35 (1H, m), 2.61-2.68 (1H, m), 4.47 (1H, dd,J=11.2, 3.2 Hz), 6.84 (1H, td, J=8.9, 4.6 Hz), 6.95-7.28 (7H, m), 7.35(2H, d, J=8.5 Hz), 7.48 (2H, d, J=8.5 Hz).

IR (ATR) cm⁻¹: 3082, 2965, 2931, 2869, 1583, 1494, 1475, 1425, 1394,1315, 1278, 1224, 1182, 1151, 1081, 1012.

mp: 112-114° C.

MS m/z: 435 (M⁺+H).

Anal. calcd for C₂₃H₂₁ClF₂O₂S: C, 63.52; H, 4.87; Cl, 8.15; F, 8.74; S,7.37. Found: C, 63.34; H, 4.85; Cl, 8.41; F, 8.75; S, 7.53.

Example 3032-[1-(4-chlorophenylsulfonyl)-4-phenylpentyl]-1,4-difluorobenzene(Isomer 303-A and Isomer 303-B)

In a similar manner to Example 299 except for the use of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (150 mg, 0.496mmol) obtained in Example 5, DL-3-phenyl-1-butanol (153 μl, 0.991 mmol)and cyanomethylenetri-n-butylphosphorane (239 μl, 0.991 mmol), the titleIsomer 303-A (low-polarity compound) (44 mg, 0.101 mmol, 21%) wasobtained as colorless plate crystals and the title Isomer 303-B(high-polarity compound) (45 mg, 0.103 mmol, 21%) was obtained as awhite powder.

Isomer 303-A

¹H-NMR (400 MHz, CDCl₃) δ: 1.21 (3H, d, J=6.7 Hz), 1.38-1.61 (2H, m),2.03-2.09 (1H, m), 2.24-2.33 (1H, m), 2.64-2.69 (1H, m), 4.40 (1H, dd,J=11.3, 3.9 Hz), 6.83 (1H, td, J=9.1, 4.4 Hz), 6.94-7.28 (7H, m), 7.35(2H, d, J=8.6 Hz), 7.47 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 2933, 1494, 1475, 1427, 1394, 1315, 1276, 1228, 1141,1085, 1012.

mp: 135-137° C.

MS m/z: 435 (M⁺+H).

Anal. calcd for C₂₃H₂₁ClF₂O₂S: C, 63.52; H, 4.87; Cl, 8.15; F, 8.74; S,7.37. Found: C, 63.37; H, 4.79; Cl, 8.18; F, 8.82; S, 7.61.

Isomer 303-B

¹H-NMR (400 MHz, CDCl₃) δ: 1.19 (3H, d, J=6.8 Hz), 1.37-1.59 (2H, m),1.83-1.93 (1H, m), 2.26-2.34 (1H, m), 2.61-2.68 (1H, m), 4.47 (1H, dd,J=11.8, 2.7 Hz), 6.83 (1H, td, J=8.9, 4.3 Hz), 6.93-7.28 (7H, m), 7.34(2H, d, J=8.6 Hz), 7.47 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 3083, 2933, 1494, 1475, 1425, 1394, 1315, 1278, 1224,1182, 1151, 1012.

mp: 111-113° C.

MS m/z: 435 (M⁺+H).

Anal. calcd for C₂₃H₂₁ClF₂O₂S: C, 63.52; H, 4.87; Cl, 8.15; F, 8.74; S,7.37. Found: C, 63.39; H, 4.84; Cl, 8.50; F, 8.82; S, 7.51.

Example 3042-[1-(4-Chlorophenylsulfonyl)-3-phenylpropyl]-1,4-difluorobenzene

Under an argon atmosphere, the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330mmol) obtained in Example 5, and 2-phenylethyl alcohol (79.2 μl, 0.661mmol) were dissolved in toluene (3 ml), followed by the addition ofcyanomethylenetri-n-butylphosphorane (159 μl, 0.661 mmol). The resultingmixture was heated under reflux for 13 hours under an argon atmosphere.The reaction mixture was then concentrated. The residue thus obtainedwas subjected to flash chromatography on a silica gel column and thefraction obtained from the hexane:ethyl acetate=93:7 eluate wasconcentrated. The solid thus obtained was washed with hexane, wherebythe title compound (100 mg, 0.246 mmol, 74%) was obtained as a whitepowder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.37-2.52 (2H, m), 2.60-2.78 (2H, m),4.44-4.49 (1H, m), 6.85 (1H, td, J=9.0, 4.5 Hz), 6.77-7.29 (7H, m), 7.36(2H, d, J=8.6 Hz), 7.49 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 3068, 1583, 1496, 1477, 1457, 1423, 1394, 1315, 1278,1214, 1176, 1147, 1081, 1012.

mp: 111-113° C.

MS m/z: 407 (M⁺+H).

Anal. calcd for C₂₁H₁₇ClF₂O₂S: C, 61.99; H, 4.21; Cl, 8.71; F, 9.34; S,7.88. Found: C, 61.76; H, 4.16; Cl, 8.88; F, 9.37; S, 8.02.

Example 3052-[1-(4-Chlorophenylsulfonyl)-3-(2-methylphenyl)propyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of2-(2-methylphenyl)ethanol (89.0 μl, 0.661 mmol), the title compound (108mg, 0.257 mmol, 78%) was obtained as colorless plate crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 2.18 (3H, s), 2.29-2.39 (1H, m), 2.46-2.62(2H, m), 2.67-2.75 (1H, m), 4.53 (1H, dd, J=11.1, 2.6 Hz), 6.86 (1H, td,J=9.0, 4.4 Hz), 6.96-7.12 (5H, m), 7.28 (1H, ddd, J=8.7, 5.4, 3.2 Hz),7.37 (2H, d, J=8.6 Hz), 7.51 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 3091, 2946, 1583, 1573, 1496, 1425, 1392, 1311, 1276,1213, 1151, 1143, 1083, 1010.

mp: 105-106° C.

MS m/z: 421 (M⁺+H).

Anal. calcd for C₂₂H₁₉ClF₂O₂S: C, 62.78; H, 4.55; Cl, 8.42; F, 9.03; S,7.62. Found: C, 62.48; H, 4.63; Cl, 8.52; F, 9.16; S, 7.75.

Example 3062-[1-(4-Chlorophenylsulfonyl)-3-(3-methylphenyl)propyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of2-(3-methylphenyl)ethanol (90.0 μl, 0.661 mmol), the title compound (115mg, 0.273 mmol, 83%) was obtained as colorless plate crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 2.29 (3H, s), 2.35-2.48 (2H, m), 2.56-2.64(1H, m), 2.68-2.77 (1H, m), 4.46-4.49 (1H, m), 6.83-6.88 (3H, m),6.97-7.03 (2H, m), 7.14 (1H, t, J=7.8 Hz), 7.26 (1H, ddd, J=8.7, 5.4,3.3 Hz), 7.36 (2H, d, J=8.6 Hz), 7.49 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 3072, 2969, 1581, 1496, 1475, 1423, 1394, 1319, 1276,1211, 1147, 1081, 1012.

mp: 87-88° C.

MS m/z: 421 (M⁺+H).

Anal. calcd for C₂₂H₁₉ClF₂O₂S: C, 62.78; H, 4.55; Cl, 8.42; F, 9.03; S,7.62. Found: C, 62.58; H, 4.60; Cl, 8.49; F, 9.21; S, 7.77.

Example 3072-[1-(4-Chlorophenylsulfonyl)-3-(4-methylphenyl)propyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of2-(4-methylphenyl)ethanol (91.9 μl, 0.661 mmol), the title compound (106mg, 0.251 mmol, 76%) was obtained as colorless columnar crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 2.31 (3H, s), 2.34-2.46 (2H, m), 2.57-2.65(1H, m), 2.67-2.72 (1H, m), 4.46-4.48 (1H, m), 6.85 (1H, td, J=9.0, 4.5Hz), 6.92 (2H, d, J=8.1 Hz), 6.97-7.03 (1H, m), 7.06 (2H, d, J=8.1 Hz),7.25 (1H, ddd, J=8.7, 5.3, 3.3 Hz), 7.35 (2H, d, J=8.6 Hz), 7.45 (2H, d,J=8.6 Hz).

IR (ATR) cm⁻¹: 3070, 2935, 1585, 1496, 1486, 1423, 1394, 1321, 1292,1278, 1216, 1182, 1147, 1083, 1014.

mp: 82-84° C.

MS m/z: 421 (M⁺+H).

Anal. calcd for C₂₂H₁₉ClF₂O₂S: C, 62.78; H, 4.55; Cl, 8.42; F, 9.03; S,7.62. Found: C, 62.67; H, 4.60; Cl, 8.31; F, 8.95; S, 7.79.

Example 3082-[1-(4-Chlorophenylsulfonyl)-3-(4-methoxyphenyl)propyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of2-(4-methoxyphenyl)ethanol (100 mg, 0.661 mmol), the title compound (86mg, 0.197 mmol, 60%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.36-2.44 (2H, m), 2.57-2.75 (2H, m), 3.79(3H, s), 4.36-4.47 (1H, m), 6.78 (2H, d, J=8.3 Hz), 6.84 (1H, td, J=8.8,4.3 Hz), 6.93 (2H, d, J=8.3 Hz), 6.97-7.03 (1H, m), 7.24-7.28 (1H, m),7.35 (2H, d, J=8.1 Hz), 7.47 (2H, d, J=8.1 Hz). IR (ATR) cm⁻¹: 3089,2954, 2836, 1612, 1583, 1513, 1494, 1459, 1427, 1394, 1322, 1270, 1245,1222, 1180, 1153, 1083, 1031, 1012.

mp: 118-120° C.

MS m/z: 436 (M⁺).

FAB-MS: 436.0717 (Calcd for C₂₂H₁₉ClF₂O₃S: 436.0712).

Anal. calcd for C₂₂H₁₉ClF₂O₃S: C, 60.48; H, 4.38; Cl, 8.11; F, 8.70; S,7.34. Found: C, 60.00; H, 4.34; Cl, 8.39; F, 8.99; S, 7.60.

Example 3092-[1-(4-Chlorophenylsulfonyl)-3-(4-fluorophenyl)propyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of2-(4-fluorophenyl)ethanol (82.5 μl, 0.661 mmol), the title compound (70mg, 0.165 mmol, 50%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.34-2.50 (2H, m), 2.61-2.76 (2H, m), 4.43(1H, dd, J=11.2, 2.9 Hz), 6.83 (1H, td, J=8.9, 4.4 Hz), 6.92-7.03 (5H,m), 7.24-7.28 (1H, m), 7.35 (2H, d, J=8.6 Hz), 7.47 (2H, d, J=8.6 Hz).IR (ATR) cm⁻¹: 3079, 1583, 1509, 1492, 1477, 1423, 1394, 1317, 1276,1251, 1216, 1176, 1145, 1081, 1012.

mp: 131-132° C.

MS m/z: 425 (M⁺).

Anal. calcd for C₂₁H₁₆ClF₃O₂S: C, 59.37; H, 3.80; Cl, 8.34; F, 13.41; S,7.55. Found: C, 59.41; H, 3.85; Cl, 8.64; F, 13.33; S, 7.67.

Example 3102-[3-(4-Chlorophenyl)-1-(4-chlorophenylsulfonyl)propyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of2-(4-chlorophenyl)ethanol (89.3 μl, 0.661 mmol), the title compound (103mg, 0.233 mmol, 71%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.35-2.50 (2H, m), 2.62-2.77 (2H, m),4.42-4.43 (1H, m), 6.84 (1H, td, J=9.0, 4.4 Hz), 6.97 (2H, d, J=8.6 Hz),6.96-7.04 (1H, m), 7.22 (2H, d, J=8.6 Hz), 7.23-7.28 (1H, m), 7.36 (2H,d, J=8.6 Hz), 7.48 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 3079, 2931, 1581, 1492, 1475, 1461, 1425, 1394, 1317,1274, 1214, 1178, 1139, 1083, 1012.

mp: 124-126° C.

MS m/z: 441 (M⁺+H).

Anal. calcd for C₂₁H₁₆Cl₂F₂O₂S: C, 57.15; H, 3.65; Cl, 16.07; F, 8.61;S, 7.27. Found: C, 56.96; H, 3.68; Cl, 16.28; F, 8.78; S, 7.44.

Example 3112-[3-(4-Bromophenyl)-1-(4-chlorophenylsulfonyl)propyl]1,4-difluorobenzene

In a similar manner to Example 304 except for the use of2-(4-bromophenyl)ethanol (89.7 μl, 0.661 mmol), the title compound (97mg, 0.200 mmol, 61%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.34-2.49 (2H, m), 2.58-2.76 (2H, m),4.42-4.45 (1H, m), 6.84 (1H, td, J=9.0, 4.3 Hz), 6.92 (2H, d, J=8.1 Hz),6.98-7.04 (1H, m), 7.26 (1H, ddd, J=8.3, 5.5, 3.4 Hz), 7.36 (2H, d,J=8.3 Hz), 7.38 (2H, d, J=8.1 Hz), 7.48 (2H, d, J=8.3 Hz).

IR (ATR) cm⁻¹: 3081, 2927, 1573, 1486, 1459, 1425, 1396, 1317, 1272,1247, 1216, 1178, 1139, 1083, 1010.

mp: 122-124° C.

MS m/z: 486 (M⁺+H).

FAB-MS: 485.9728 (Calcd for C₂₁H₁₆ClBrF₂O₂S: 485.9690).

Example 3122-[1-(4-Chlorophenylsulfonyl)-4-phenylbutyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of3-phenyl-1-propanol (90.0 μl, 0.661 mmol), the title compound (106 mg,0.251 mmol, 76%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.50-1.65 (2H, m), 2.06-2.16 (1H, m),2.40-2.49 (1H, m), 2.53-2.69 (2H, m), 4.52 (1H, dd, J=11.4, 3.1 Hz),6.83 (1H, td, J=9.0, 4.5 Hz), 6.94-7.00 (1H, m), 7.05-7.26 (6H, m), 7.37(2H, d, J=8.6 Hz), 7.52 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 3070, 2956, 2861, 1914, 1583, 1488, 1461, 1423, 1392,1319, 1278, 1249, 1207, 1174, 1143, 1081, 1012.

mp: 107-108° C.

MS m/z: 421 (M⁺+H).

FAB-MS: 421.0834 (Calcd for C₂₂H₂₀ClF₂O₂S: 421.0841).

Example 3132-[1-(4-Chlorophenylsulfonyl)-5-phenylpentyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of4-phenyl-1-butanol (102 μl, 0.661 mmol), the title compound (107 mg,0.246 mmol, 75%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.26 (2H, q, J=7.6 Hz), 1.57-1.67 (2H, m),2.06-2.16 (1H, m), 2.40-2.62 (3H, m), 4.49 (1H, dd, J=12.0, 3.3 Hz),6.81 (1H, td, J=9.0, 4.5 Hz), 6.94-7.00 (1H, m), 7.08-7.26 (6H, m), 7.37(2H, d, J=8.3 Hz), 7.52 (2H, d, J=8.3 Hz).

IR (ATR) cm⁻¹: 2942, 2856, 1583, 1494, 1475, 1463, 1427, 1394, 1324,1276, 1240, 1211, 1182, 1151, 1083, 1049, 1014.

mp: 88-90° C.

MS m/z: 435 (M⁺+H).

Anal. calcd for C₂₃H₂₁ClF₂O₂S: C, 63.52; H, 4.87; Cl, 8.15; F, 8.74; S,7.37. Found: C, 63.32; H, 4.74; Cl, 8.19; F, 8.93; S, 7.65.

Example 3142-[1-(4-Chlorophenylsulfonyl)-2-(4-fluorophenyl)ethyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of 4-fluorobenzylalcohol (71.2 μl, 0.661 mmol), the title compound (118 mg, 0.287 mmol,87%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 3.29 (1H, dd, J=14.0, 12.0 Hz), 3.81 (1H, dd,J=14.0, 3.7 Hz), 4.75 (1H, dd, J=12.0, 3.7 Hz), 6.70 (1H, td, J=9.0, 4.5Hz), 6.84-7.00 (6H, n), 7.38 (2H, d, J=8.6 Hz), 7.56 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 3079, 2964, 1600, 1573, 1511, 1492, 1427, 1392, 1307,1278, 1220, 1172, 1143, 1081, 1010.

mp: 151-153° C.

MS m/z: 411 (M⁺+H).

Anal. calcd for C₂₀H₁₄ClF₃O₂S: C, 58.47; H, 3.43; Cl, 8.63; F, 13.87; S,7.80. Found: C, 58.27; H, 3.39; Cl, 8.80; F, 13.80; S, 8.00.

Example 3152-[1-(4-Chlorophenylsulfonyl)-3-cyclopentylpropyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of2-cyclopentane-ethanol (81.9 μl, 0.661 mmol), the title compound (79 mg,0.186 mmol, 60%) was obtained as colorless plate crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94-1.07 (4H, m), 1.09-1.18 (1H, m),1.23-1.33 (1H, m), 1.45-1.59 (3H, m), 1.67-1.79 (2H, m), 2.03-2.14 (1H,m), 2.41-2.50 (1H, m), 4.49 (1H, dd, J=12.2, 2.9 Hz), 6.82 (1H, td,J=9.0, 4.4 Hz), 6.94-7.00 (1H, m), 7.22-7.26 (1H, m), 7.37 (2H, d, J=8.8Hz), 7.52 (2H, d, J=8.8 Hz). IR (ATR) cm⁻¹: 2952, 2852, 1583, 1494,1475, 1427, 1396, 1313, 1278, 1214, 1176, 1147, 1081, 1014.

mp: 93-94° C.

MS m/z: 399 (M⁺+H).

FAB-MS: 399.1004 (Calcd for C₂₀H₂₂ClF₂O₂S: 399.0997).

Example 3162-[1-(4-Chlorophenylsulfonyl)-3-cyclohexylpropyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of2-cyclohexane-ethanol (92.0 μl, 0.661 mmol), the title compound (86 mg,0.208 mmol, 63%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 0.75-0.89 (2H, m), 0.97-1.25 (6H, m),1.61-1.68 (5H, m), 2.01-2.12 (1H, m), 2.42-2.50 (1H, m), 4.46 (1H, dd,J=11.5, 2.9 Hz), 6.82 (1H, td, J=9.3, 4.4 Hz), 6.94-7.00 (1H, m),7.20-7.26 (1H, m), 7.37 (2H, d, J=8.1 Hz), 7.52 (2H, d, J=8.1 Hz). IR(ATR) cm⁻¹: 2925, 2842, 1581, 1496, 1450, 1423, 1392, 1315, 1276, 1238,1176, 1149, 1085, 1010.

mp: 82-83° C.

MS m/z: 413 (M⁺+H).

Anal. calcd for C₂₁H₂₃ClF₂O₂S: C, 61.08; H, 5.61; Cl, 8.59; F, 9.20; S,7.77. Found: C, 60.80; H, 5.58; Cl, 8.79; F, 9.45; S, 7.92.

Example 3172-[1-(4-Chlorophenylsulfonyl)-4-cyclohexylbutyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of3-cyclohexyl-1-propanol (103 μl, 0.661 mmol), the title compound (96 mg,0.224 mmol, 68%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 0.72-1.73 (15H, m), 2.01-2.12 (1H, m),2.33-2.41 (1H, m), 4.51 (1H, d, J=9.0 Hz), 6.80-6.86 (1H, m), 6.94-7.00(1H, m), 7.22-7.26 (1H, m), 7.38 (2H, d, J=7.8 Hz), 7.53 (2H, d, J=7.8Hz).

IR (ATR) cm⁻¹: 2919, 2852, 1583, 1496, 1488, 1475, 1425, 1394, 1317,1274, 1236, 1207, 1149, 1081, 1012.

mp: 47-49° C.

MS m/z: 427 (M⁺+H).

FAB-MS: 427.1342 (Calcd for C₂₂H₂₆ClF₂O₂S: 427.1310

Example 3182-[3-(4-chlorophenylsulfonyl)-3-(2,5-difluorophenyl)propyl]pyridine

In a similar manner to Example 304 except for the use of2-(2-hydroxyethyl)pyridine (74.5 μl, 0.661 mmol), the title compound (74mg, 0.181 mmol, 55%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.49-2.58 (1H, m), 2.68-2.93 (3H, m), 4.60(1H, dd, J=10.9, 3.3 Hz), 6.84 (1H, td, J=8.9, 4.5 Hz), 6.95-7.00 (1H,m), 7.03 (1H, d, J=7.6 Hz), 7.11 (1H, dd, J=6.9, 5.1 Hz), 7.29-7.38 (1H,m), 7.39 (2H, d, J=8.6 Hz), 7.54 (2H, d, J=8.6 Hz) 7.51-7.58 (1H, m),8.48 (1H, d, J=3.9 Hz).

IR (ATR) cm⁻¹: 3075, 1585, 1569, 1496, 1473, 1425, 1394, 1311, 1278,1205, 1145, 1081, 1012.

mp: 129-131° C.

MS m/z: 408 (M⁺+H).

FAB-MS: 408.0649 (Calcd for C₂₀H₁₇ClF₂NO₂S: 408.0637).

Anal. calcd for C₂₀H₁₆ClF₂NO₂S: C, 58.90; H, 3.95; Cl, 8.69; F, 9.32; N,3.42; S, 7.86. Found: C, 58.57; H, 3.87; Cl, 8.90; F, 9.34; N, 3.53; S,7.96.

Example 3195-[3-(4-Chlorophenylsulfonyl)-3-(2,5-difluorophenyl)propyl]-4-methyl-1,3-thiazole

In a similar manner to Example 304 except for the use of5-(2-hydroxyethyl)-4-methylthiazole (78.9 μl, 0.661 mmol), the titlecompound (87 mg, 0.203 mmol, 62%) was obtained as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ: 2.21 (3H, s), 2.36-2.47 (1H, m), 2.70-2.87(3H, m), 4.49 (1H, dd, J=10.9, 2.6 Hz), 6.86 (1H, td, J=9.1, 4.4 Hz),6.99-7.05 (1H, m), 7.24-7.28 (1H, m), 7.39 (2H, d, J=8.8 Hz), 7.51 (2H,d, J=8.8 Hz) 8.57 (1H, s).

IR (ATR) cm⁻¹: 3085, 2933, 1583, 1571, 1494, 1477, 1405, 1315, 1278,1220, 1147, 1083, 1012.

mp: 183-184° C.

MS m/z: 428 (M⁺+H).

FAB-MS: 428.0355 (Calcd for C₂₉H₁₇ClF₂NO₂S₂: 428.0357).

Example 3201-[3-(4-Chlorophenylsulfonyl)-3-(2,5-difluorophenyl)propyl]piperidine

In a similar manner to Example 304 except for the use of1-piperidine-ethanol (87.3 μl, 0.661 mmol), the title compound (32 mg,0.0773 mmol, 23%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.34-1.40 (2H, m), 1.44-1.49 (4H, m),2.09-2.34 (7H, m), 2.59-2.67 (1H, m), 4.76-4.79 (1H, m), 6.83 (1H, td,J=9.0, 4.3 Hz), 6.94-7.00 (1H, m), 7.23 (1H, ddd, J=8.9, 5.8, 3.7 Hz),7.39 (2H, d, J=8.8 Hz), 7.55 (2H, d, J=8.8 Hz).

IR (ATR) cm⁻¹: 2942, 2800, 2761, 1579, 1492, 1427, 1396, 1355, 1309,1284, 1243, 1189, 1118, 1085, 1014.

mp: 106-107° C.

MS m/z: 414 (M⁺+H).

FAB-MS: 414.1118 (Calcd for C₂₀H₂₃ClF₉NO₂S: 414.1106).

Anal. calcd for C₂₀H₂₂ClF₂NO₂S: C, 58.04; H, 5.36; Cl, 8.57; F, 9.18; N,3.38; S, 7.75. Found: C, 57.76; H, 5.34; Cl, 8.79; F, 9.44; N, 3.39; S,7.89.

Example 3212-[3-(4-Chlorophenylsulfonyl)-3-(2,5-difluorophenyl)propyl]-5,5-dimethyl-1,3-dioxane

In a similar manner to Example 304 except for the use of5,5-dimethyl-1,3-dioxane-2-ethanol (103 μl, 0.661 mmol), the titlecompound (72 mg, 0.162 mmol, 49%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 0.70 (3H, s), 1.12 (3H, s), 1.53-1.58 (2H,m), 2.15-2.25 (1H, m), 2.55-2.65 (1H, m), 3.35 (2H, d, J=10.7 Hz), 3.55(2H, d, J=10.7 Hz), 4.39 (1H, t, J=4.4 Hz), 4.64 (1H, dd, J=11.2, 3.4Hz), 6.83 (1H, td, J=8.9, 4.6 Hz), 6.94-7.00 (1H, m), 7.21-7.26 (1H, m),7.38 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 2958, 2842, 1583, 1498, 1467, 1396, 1317, 1278, 1214,1147, 1130, 1081, 1041, 1012.

mp: 69-71° C.

MS m/z: 445 (M⁺+H).

FAB-MS: 445.1031 (Calcd for C₂₁H₂₄ClF₂O₄S: 445.1052).

Anal. calcd for C₂₁H₂₃ClF₂O₄S: C, 56.69; H, 5.21; Cl, 7.97; F, 8.54; S,7.21. Found: C, 56.29; H, 5.16; Cl, 8.09; F, 8.73; S, 7.43.

Example 322 2-[1-(4-Chlorophenylsulfonyl)hexyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of 1-pentanol(71.8 μl, 0.661 mmol), the title compound (88 mg, 0.236 mmol, 72%) wasobtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 0.83-0.45 (2H, m), 1.18-1.31 (7H, m),2.03-2.12 (1H, m), 2.37-2.46 (1H, m), 4.50 (1H, dd, J=11.4, 3.3 Hz),6.82 (1H, td, J=9.0, 4.5 Hz), 6.95-7.00 (1H, m), 7.22-7.26 (1H, m), 7.37(2H, d, J=8.6 Hz), 7.52 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 2946, 2923, 2867, 1585, 1494, 1477, 1425, 1396, 1317,1278, 1247, 1211, 1176, 1149, 1081, 1014.

mp: 68-69° C.

MS m/z: 373 (M⁺+H).

Anal. calcd for C₁₈H₁₉ClF₂O₂S: C, 57.98; H, 5.14; Cl, 9.51; F, 10.19; S,8.60. Found: C, 57.71; H, 5.14; Cl, 9.65; F, 10.31; S, 8.73.

Example 323 2-[1-(4-Chlorophenylsulfonyl)heptyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of 1-hexanol (82.2μl, 0.661 mmol), the title compound (69 mg, 0.178 mmol, 54%) wasobtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 0.84 (3H, t, J=7.0 Hz), 1.17-1.31 (8H, m),2.03-2.13 (1H, m), 2.38-2.46 (1H, m), 4.50 (1H, dd, J=11.1, 3.0 Hz),6.81 (1H, td, J=9.0, 4.5 Hz), 6.94-7.00 (1H, m), 7.23 (1H, ddd, J=8.6,5.3, 3.1 Hz), 7.37 (2H, d, J=8.6 Hz), 7.52 (2H, d, J=8.6 Hz). IR (ATR)cm⁻¹: 2962, 2925, 2856, 1583, 1492, 1477, 1425, 1394, 1315, 1276, 1243,1214, 1174, 1149, 1081, 1012.

mp: 77-78° C.

MS m/z: 387 (M⁺+H).

Anal. calcd for C₁₉H₂₁ClF₂O₂S: C, 58.98; H, 5.47; Cl, 9.16; F, 9.82; S,8.29. Found: C, 58.82; H, 5.54; Cl, 9.31; F, 9.86; S, 8.44.

Example 324 2-[1-(4-chlorophenylsulfonyl)octyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of 1-heptanol(93.5 μl, 0.661 mmol), the title compound (107 mg, 0.267 mmol, 81%) wasobtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 0.85 (3H, t, J=7.0 Hz), 1.15-1.27 (10H, m),2.03-2.12 (1H, m), 2.38-2.46 (1H, m), 4.50 (1H, dd, J=11.5, 2.7 Hz),6.82 (1H, td, J=9.0, 4.6 Hz), 6.94-7.00 (1H, m), 7.24 (1H, ddd, J=8.7,5.3, 3.1 Hz), 7.38 (2H, d, J=8.6 Hz), 7.53 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 2925, 2859, 1583, 1496, 1475, 1469, 1425, 1394, 1322,1274, 1241, 1205, 1147, 1081, 1012.

mp: 47-48° C.

MS m/z: 401 (M⁺+H).

Anal. calcd for C₂₀H₂₃ClF₂O₂S: C, 59.92; H, 5.78; Cl, 8.84; F, 9.48; S,8.00. Found: C, 59.63; H, 5.61; Cl, 8.96; F, 9.59; S, 8.17.

Example 3252-[1-(4-Chlorophenylsulfonyl)-5-methylhexyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of4-methyl-1-pentanol (83.2 μl, 0.661 mmol), the title compound (122 mg,0.315 mmol, 96%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 0.78 (3H, d, J=6.6 Hz), 0.81 (3H, d, J=6.6Hz), 1.14-1.25 (4H, m), 1.41-1.52 (1H, m), 2.02-2.12 (1H, m), 2.35-2.41(1H, m), 4.51 (1H, dd, J=11.6, 2.6 Hz), 6.83 (1H, td, J=9.0, 4.4 Hz),6.95-7.00 (1H, m), 7.24 (1H, ddd, J=8.9, 5.6, 3.2 Hz), 7.38 (2H, d,J=8.6 Hz), 7.53 (2H, d, J=8.6 Hz).

IR (ATR) cm⁻¹: 2962, 2925, 2898, 2861, 1583, 1492, 1465, 1427, 1394,1315, 1278, 1247, 1211, 1176, 1147, 1081, 1014.

mp: 79-80° C.

MS m/z: 387 (M⁺+H).

Anal. calcd for C₁₉H₂₁ClF₂O₂S: C, 58.98; H, 5.47; Cl, 9.16; F, 9.82; S,8.29. Found: C, 58.92; H, 5.42; Cl, 9.28; F, 10.00; S, 8.45.

Example 3262-[1-(4-Chlorophenylsulfonyl)-4-methylhexyl]-1,4-difluorobenzene

In a similar manner to Example 304 except for the use of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.660mmol) obtained in Example 5, 3-methyl-1-pentanol (180 μl, 1.32 mmol),and cyanomethylenetri-n-butylphosphorane (163 μl, 1.32 mmol), the titlecompound (217 mg, 0.561 mmol, 85%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 0.77-0.85 (6H, m), 1.07-1.15 (2H, m),1.21-1.33 (3H, m), 1.98-2.15 (1H, m), 2.39-2.52 (1H, m), 4.44-4.49 (1H,m), 6.82 (1H, td, J=8.9, 4.1 Hz), 6.94-7.00 (1H, m), 7.23-7.26 (1H, m),7.38 (2H, d, J=8.3 Hz), 7.53 (2H, d, J=8.3 Hz).

IR (ATR) cm⁻¹: 2960, 2919, 2873, 1583, 1496, 1473, 1461, 1425, 1394,1319, 1278, 1216, 1153, 1083, 1012.

mp: 56-58° C.

MS m/z: 387 (M⁺+H).

Anal. calcd for C₁₉H₂₁ClF₂O₂S: C, 58.98; H, 5.47; Cl, 9.16; F, 9.82; S,8.29. Found: C, 58.87; H, 5.55; Cl, 9.12; F, 9.93; S, 8.42.

Referential Example 45 5-Dibromomethyl-2-(2,5-difluorobenzoyl)pyridine(Compound A) and 5-bromomethyl-2-(2,5-difluorobenzoyl)pyridine (CompoundB)

Compound A Compound B

While heating under reflux, N-bromosuccinimide (17.0 g, 95.7 mmol) and acatalytic amount of 2,2′-azobis(2-methylpropionitrile) were added to asolution of the 2-[(2,5-difluorophenyl)-hydroxymethyl]-5-methylpyridine(7.50 g, 31.9 mmol), which had been obtained in Referential Example 15,in carbon tetrachloride (100 ml). The mixture was then stirred. Afterreflux for 24 hours, the reaction mixture was cooled to roomtemperature. The precipitate thus obtained was separated by filtration.The precipitate was then added to an aqueous solution of sodiumthiosulfate and the resulting mixture was extracted with chloroform. Thesolution was washed with a saturated aqueous solution of sodiumbicarbonate and brine, and then dried over sodium sulfate. The residueobtained by concentrating the solution under reduced pressure waspurified by silica gel chromatography (hexane:ethyl acetate=10:1) toyield the title compound A (3.91 g, 31%) and the title compound B (3.34g, 34%) as oils.

Compound A

¹H-NMR (400 MHz, CDCl₃) δ: 6.70 (1H, s), 7.12 (1H, m), 7.24 (1H, m),7.39 (1H, m), 8.12 (1H, d, J=8.4 Hz), 8.19 (1H, dd, J=2.0, 8.4 Hz), 8.77(1H, d, J=2.0 Hz).

IR (ATR) cm⁻¹: 1676, 1487, 1421, 1311, 1193, 827.

MS m/z: 392 (M⁺+H).

Compound B

¹H-NMR (400 MHz, CDCl₃) δ: 4.52 (2H, s), 7.12 (1H, m), 7.21 (1H, m),7.39 (1H, m), 7.94 (1H, dd, J=2.0, 8.0 Hz), 8.08 (1H, d, J=8.0 Hz), 8.67(1H, d, J=2.0 Hz).

MS m/z: 313 (M⁺+H).

Referential Example 46[6-(2,5-Difluorophenylcarbonyl)pyridin-3-yl]methyl acetate

While heating under reflux, N-bromosuccinimide (6.0 g, 33.6 mmol) and acatalytic amount of 2,2′-azobis(2-methylpropionitrile) were added to asolution of the 2-[(2,5-difluorophenyl)-hydroxymethyl]-5-methylpyridine(2.64 g, 11.2 mmol), which had been obtained in Referential Example 15,in carbon tetrachloride (60 ml). The resulting mixture was then stirred.After reflux for 7 hours, the reaction mixture was cooled to roomtemperature and added to an aqueous solution of sodium thiosulfate. Themixture was extracted with ether. The solution was washed with water andbrine, and then dried over sodium sulfate. The residue obtained byconcentrating the solution under reduced pressure was dissolved intoluene and the resulting solution was concentrated again. The residuewas dissolved in N,N-dimethylformamide (20 ml). Sodium acetate (4.59 g,56 mmol) was added to the resulting solution and the mixture was stirredat 70° C. for 17 hours. After cooling, the reaction mixture wasdissolved in ethyl acetate (100 ml), followed by washing with water andbrine. The solution was dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel chromatography (hexane:ethyl acetate=5:1) to yield the titlecompound (600 mg, 18%) as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 2.12 (3H, s), 5.19 (2H, s), 7.10 (1H, m),7.19 (1H, m), 7.37 (1H, s), 7.88 (1H, dd, J=2.4, 8.0 Hz), 8.07 (1H, d,J=8.0 Hz), 8.62 (1H, d, J=2.4 Hz).

IR (ATR) cm⁻¹: 1739, 1678, 1489, 1222, 821.

MS m/z: 292 (M⁺+H).

Example 3272-[(4-Chlorophenylthio)-(2,5-difluorophenyl)methyl]-5-[(4-chlorophenylthio)methyl]pyridine

A suspension of sodium borohydride (33 mg, 0.88 mmol) in ethanol (15 ml)was cooled to −78° C. While stirring, an ethanol solution (10 ml) of[6-(2,5-difluorophenylcarbonyl)pyridin-3-yl]methyl acetate (510 mg, 1.75mmol) was added in portions. After stirring for 30 minutes, an aqueoussolution of ammonium chloride was added and the resulting mixture wasallowed to stand until the temperature of the mixture increased to roomtemperature. The resulting mixture was extracted with ethyl acetate (100ml), followed by washing with water and brine, drying over anhydrousmagnesium sulfate and concentration under reduced pressure. The residuewas dissolved in methylene chloride (30 ml) and under ice cooling,triethylamine (2701) and methanesulfonyl chloride (270 μl) were addedthereto. The resulting mixture was stirred at room temperature for 3days. Water was added and the mixture was extracted with ethyl acetate(60 ml). The solution was washed with water and brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure.

The residue was dissolved in N,N-dimethylformamide (25 ml). Undernitrogen atmosphere, 4-chlorobenzenethiol (751 mg, 5.3 mmol) andpotassium carbonate (718 mg, 5.2 mmol) were added and the mixture wasstirred at 60° C. for 1 hour. After the reaction mixture was cooled toroom temperature, diethyl ether (80 ml) was added thereto. The resultingmixture was washed with water and brine, dried over magnesium sulfateand concentrated under reduced pressure. The residue was subjected tosilica gel chromatography (hexane:ethyl acetate=10:1) to yield the titlecompound (237 mg, 27%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 3.99 (2H, s), 5.81 (1H, s), 6.90 (2H, m),7.15 (2H, d, J=8.8 Hz), 7.16 (2H, d, J=8.8 Hz), 7.19 (4H, d, J=8.8 Hz),7.20 (1H, d, J=7.6 Hz), 7.38 (1H, m), 7.49 (1H, dd, J=2.0, 7.6 Hz), 8.38(1H, br).

IR (ATR) cm⁻¹: 1473, 1385, 1092, 1010, 814.

mp: 87-88° C.

Example 3282-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-5-[(4-chlorophenylsulfonyl)methyl]pyridine

To a solution of2-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-5-[(4-chlorophenylthio)methyl]pyridine(75 mg, 0.15 mmol) in methanol (6.0 ml) were successively addedhexaammonium heptamolybdate tetrahydrate (30 mg) and a 30% aqueoushydrogen peroxide solution (3 ml). The resulting mixture was stirred for22 hours. Ethyl acetate was added to the reaction mixture. The resultingmixture was washed with water, an aqueous solution of sodium thiosulfateand brine. After drying the solution, it was concentrated under reducedpressure. The residue was purified by silica gel chromatography (2%MeOH/CHCl₃) to yield the title compound (70 mg, 62%) as colorless needlecrystals.

¹H-NMR (400 MHz, CDCl₃) δ: 4.29 (2H, s), 5.91 (1H, s), 6.90-7.08 (2H,m), 7.39 (2H, dd, J=1.6, 6.8 Hz), 7.45 (2H, dd, J=1.6, 6.8 Hz), 7.51(2H, d, J=8.8 Hz), 7.55 (2H, d, J=8.8 Hz), 7.60 (1H, d, J=8.0 Hz), 7.65(1H, dd, J=2.4, 8.0 Hz), 7.91 (1H, m), 8.23 (1H, s).

IR (ATR) cm⁻¹: 1495, 1322, 1149, 1087, 615.

mp: 186-187° C.

MS m/z: 568 (M⁺+H).

Anal. calcd for C₂₅H₁₇Cl₂F₂NO₄S₂: C, 52.82%; H, 3.01%; N, 2.46%; S,11.28%; Cl, 12.47%; F, 6.68%. Found: C, 52.88%; H, 3.10%; N, 2.63%; S,11.38%; Cl, 12.40%; F, 6.83%.

Referential Example 472-[(2,5-Difluorophenyl)-hydroxymethyl]-5-(1,3-dioxolan-2-yl)pyridine

To a pyridine solution (60 ml) of the5-dibromomethyl-2-(2,5-difluorobenzoyl)pyridine (Compound A) (3.91 g, 10ml) obtained in Referential Example 45 was added ethylene glycol (6.2 g,100 mmol). While heating at 90° C., the mixture was stirred for 17hours. The reaction mixture was concentrated under reduced pressure andthe residue was dissolved in ether (200 ml). The resulting solution waswashed with water, a saturated aqueous solution of sodium bicarbonateand brine and dried over anhydrous magnesium sulfate. The solution wasconcentrated under reduced pressure. The residue was dissolved inethanol (60 ml). Sodium borohydride (190 mg, 5 mmol) was added to theresulting solution under ice cooling, followed by stirring at roomtemperature for 1 hour. After the addition of water, the mixture wasextracted with ethyl acetate. The solution was washed with brine andthen dried over anhydrous magnesium sulfate. The residue obtained byconcentrating the solution under reduced pressure was purified by silicagel chromatography (hexane:ethyl acetate 5:1-1:1) to yield the titlecompound (1.52 g, 52%) as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 4.0-4.2 (4H, m), 5.84 (1H, s), 6.10 (1H, s),6.91 (1H, m), 6.99 (1H, m), 7.09 (1H, m), 7.26 (1H, d, J=8.0 Hz), 7.76(1H, dd, J=2.0, 8.0 Hz), 8.64 (1H, d, J=2.0 Hz).

IR (ATR) cm⁻¹: 1489, 1086, 1026, 818, 715.

MS m/z: 294 (M⁺+H).

Example 3292-[(4-Chlorophenylthio)-(2,5-difluorophenyl)methyl]-5-(1,3-dioxolan-2-yl)pyridine

Under nitrogen atmosphere, triethylamine (1.08 ml, 7.8 mmol) andmethanesulfonyl chloride (0.52 ml, 6.8 mmol) were added to a methylenechloride solution (30 ml) of2-[(2,5-difluorophenyl)-hydroxymethyl]-5-(1,3-dioxolan-2-yl)pyridine(1.52 g, 5.2 mmol) under ice cooling and the resulting mixture wasstirred at room temperature for 3 hours. After the addition of asaturated aqueous solution of sodium bicarbonate, the resulting mixturewas extracted with ether. The solution was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure.

The residue was dissolved in dimethylformamide (30 ml). To the resultingsolution were added chlorobenzenethiol (901 mg, 6.2 mmol) and potassiumcarbonate (1.08 g, 7.8 mmol) and the mixture was stirred at 60° C. for 3hours. After cooling to room temperature, the reaction mixture wasdiluted with ether. The solution was washed with water and brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=5:1), whereby the title compound(1.56 g, 71%) was obtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 4.0-4.15 (4H, m), 5.84 (1H, s), 5.92 (1H, s),6.85-6.96 (2H, m), 7.19 (2H, d, J=8.8 Hz), 7.25 (2H, d, J=8.8 Hz), 7.43(1H, d, J=8.0 Hz), 7.43 (1H, m), 7.77 (1H, dd, J=2.0, 8.0 Hz), 8.70 (1H,d, J=2.0 Hz).

IR (ATR) cm⁻¹: 1489, 1475, 1091, 814.

mp: 70-73° C.

MS m/z: 420 (M⁺+H).

Example 3302-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-5-(1,3-dioxolan-2-yl)pyridine

Hexaammonium heptamolybdate tetrahydrate (150 mg) was added to asolution of2-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-5-(1,3-dioxolan-2-yl)pyridine(1.54 g, 3.67 mmol) in methanol (30 ml). To the resulting mixture wasadded a 30% aqueous hydrogen peroxide solution (15 ml), followed bystirring for 24 hours. The reaction mixture was diluted with ethylacetate. The solution was washed with water and brine, and concentratedunder reduced pressure. The residue was crystallized from ethanol,whereby the title compound (1.22 g, 74%) was obtained as colorlessneedle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 4.02-4.10 (4H, m), 5.85 (1H, s), 5.97 (1H,s), 6.91 (1H, m), 6.96 (1H, m), 7.38 (2H, d, J=8.4 Hz), 7.53 (2H, d,J=8.4 Hz), 7.63 (1H, d, J=7.6 Hz), 7.82 (1H, d, J=8.0 Hz), 7.94 (1H, m),8.67 (1H, br-s).

IR (ATR) cm⁻¹: 1488, 1319, 1232, 1149, 823.

mp: 167-168° C.

MS m/z: 452 (M⁺+H).

FAB-MS: 452.0544 (Calcd for C₂₁H₁₇ClF₂NO₄S: 452.0535).

Example 3312-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-5-(hydroxymethyl)pyridine

To a 1,4-dioxane solution (30 ml) of2-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-5-(1,3-dioxolan-2-yl)pyridine(295 mg, 0.54 mmol) was added 1N hydrochloric acid (30 ml) and theresulting mixture was stirred at room temperature for 18 hours. Thereaction mixture was extracted with ethyl acetate. The extract waswashed with water, a saturated aqueous solution of sodium bicarbonateand brine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure.

The residue was dissolved in ethanol (10 ml). To the resulting solutionwas added sodium borohydride (10 mg, 0.27 mmol) under ice cooling,followed by stirring for 1 hour. Water was added and the mixture wasextracted with ethyl acetate. The extract was washed with water andbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue thus obtained was purified by silica gelchromatography (3% methanol/chloroform), whereby the title compound (205mg, 93%) was obtained as needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 4.74 (2H, s), 5.94 (1H, s), 6.91 (1H, m),6.99 (1H, m), 7.38 (2H, d, J=8.4 Hz), 7.53 (2H, d, J=8.4 Hz), 7.62 (1H,d, J=8.0 Hz), 7.76 (1H, dd, J=2.0, 8.0 Hz), 7.98 (1H, m), 8.58 (1H, d,J=2.0 Hz).

IR (ATR) cm⁻¹: 3410, 1489, 1321, 1240, 1147, 1012, 818.

mp: 151-152° C.

MS m/z: 410 (M⁺+H).

FAB-MS: 410.0444 (Calcd for C₁₉H₁₅ClF₂NO₃S: 410.0429).

Example 332 Methyl3-[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]acrylate

To a 1,4-dioxane solution (10 ml) of the2-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-5-(1,3-dioxolan-2-yl)pyridine(212 mg, 0.47 mmol) obtained in Example 330 was added 1N hydrochloricacid (10 ml) and the mixture was stirred at room temperature for 19hours. The solution was extracted with ethyl acetate. The extract waswashed with water, a saturated aqueous solution of sodium bicarbonateand brine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure.

The residue thus obtained was dissolved in tetrahydrofuran (15 ml) andunder nitrogen atmosphere, methyl(triphenylphosphoranylidene)acetate(188 mg, 0.56 mmol) was added to the resulting solution. The mixture wasstirred for 17 hours. The reaction mixture was concentrated underreduced pressure. The residue was purified by silica gel chromatography(hexane:ethyl acetate=5:1), whereby the title compound (187 mg, 86%) wasobtained as needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 3.80 (3H, s), 5.94 (1H, s), 6.50 (1H, d,J=16.0 Hz), 6.91 (1H, m), 6.99 (1H, m), 7.38 (2H, d, J=8.8 Hz), 7.53(2H, d, J=8.8 Hz), 7.63 (1H, d, J=8.0 Hz), 7.63 (1H, d, J=16.0 Hz), 7.84(1H, dd, J=2.0, 8.0 Hz), 7.98 (1H, m), 8.70 (1H, d, J=2.0 Hz).

IR (ATR) cm⁻¹: 1710, 1496, 1389, 1327, 1149, 1084, 816, 760.

mp: 145-146° C.

MS m/z: 464 (M⁺+H).

Example 333 Methyl3-[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]propionate

Methyl3-[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]acrylate(160 mg, 0.34 mmol) was dissolved in ethanol (15 ml). Palladium oncarbon (30 mg) was added and the resulting mixture was vigorouslystirred under 1 atm hydrogen atmosphere for 24 hours. The reactionmixture was filtered and then, concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (hexane:ethylacetate=5:1), whereby the title compound (94 mg, 58%) was obtained asneedle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 2.63 (2H, t, J=7.6 Hz), 2.95 (2H, t, J=7.6Hz), 3.65 (3H, s), 5.89 (1H, s), 6.90 (1H, m), 6.97 (1H, m), 7.36 (2H,d, J=8.4 Hz), 7.53 (2H, d, J=8.4 Hz), 7.55 (2H, m), 8.00 (1H, m), 8.45(1H, d, J=1.6 Hz).

IR (ATR) cm⁻¹: 1731, 1489, 1319, 1225, 1147, 821.

mp: 121-123° C.

MS m/z: 466 (M⁺+H).

Example 3343-[6-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]propionicacid

In tetrahydrofuran (5 ml) was dissolved methyl3-[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]propionate(92 mg, 0.20 mmol). An aqueous solution (3 ml) of lithium hydroxide (23mg, 0.5 mmol) was added and the mixture was stirred for 2 hours. Afterthe addition of 10% sodium bisulfate, the mixture was extracted withethyl acetate. The extract was washed with water and brine, dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The residue thus obtained was crystallized from ethanol toyield the title compound (67 mg, 75%) as needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 2.69 (2H, t, J=7.6 Hz), 2.96 (2H, t, J=7.6Hz), 5.92 (1H, s), 6.90 (1H, m), 6.98 (1H, m), 7.36 (2H, d, J=8.4 Hz),7.52 (2H, d, J=8.4 Hz), 7.56 (2H, m), 7.99 (1H, m), 8.47 (1H, d, J=2.4Hz).

IR (ATR) cm⁻¹: 1704, 1489, 1309, 1216, 1149, 1081, 827.

mp: 158-160° C.

MS m/z: 452 (M⁺+H).

Anal. calcd for C₂₁H₁₆ClF₂NO₄S: C, 55.82%; H, 3.57%; N, 3.10%; S, 7.10%;Cl, 7.85%; F, 8.41%. Found: C, 55.70%; H, 3.75%; N, 3.19%; S, 7.12%; Cl,8.64%; F, 8.11%.

Example 335[6-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde

To a 1,4-dioxane solution (30 ml) of the2-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-5-(1,3-dioxolan-2-yl)pyridine(602 mg, 1.3 mmol) obtained in Example 330 was added 1N hydrochloricacid (30 ml). The resulting mixture was stirred at room temperature for18 hours. The solution was extracted with ethyl acetate, followed bysuccessive washing with water, a saturated aqueous solution of sodiumbicarbonate and brine. The solution was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue thusobtained was purified by silica gel chromatography (hexane:ethylacetate=5:1), whereby the title compound (530 mg, 98%) was obtained asneedle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 6.01 (1H, s), 6.94 (1H, m), 7.01 (1H, m),7.40 (2H, d, J=8.4 Hz), 7.54 (2H, d, J=8.4 Hz), 7.81 (1H, d, J=8.4 Hz),7.97 (1H, m), 8.20 (1H, dd, J=2.0, 8.4 Hz), 9.05 (1H, d, J=2.0 Hz),10.12 (1H, s).

IR (ATR) cm⁻¹: 1708, 1489, 1376, 1322, 1151, 1117, 756.

Example 3362-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-5-(piperidin-1-ylmethyl)pyridine

To a methylene chloride solution (5 ml) of[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde(82 mg, 0.2 mmol) and piperidine (40 μl, 0.4 mmol) were added aceticacid (23 μl, 0.4 mmol) and sodium triacetoxyborohydride (85 mg, 0.4mmol) at room temperature. The mixture was stirred for 3 hours. Afterthe reaction was quenched by the addition of a saturated aqueoussolution of sodium bicarbonate, the mixture was diluted with ethylacetate (80 ml). The organic layer obtained by separation was washedwith water and brine, dried and then concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=1:1), followed by crystallizationfrom ethanol to yield the title compound (89 mg, 93%).

¹H-NMR (400 MHz, CDCl₃) δ: 1.5-1.6 (6H, m), 2.3-2.4 (4H, m), 3.45 (2H,s), 5.91 (1H, s), 6.90 (1H, m), 6.98 (1H, m), 7.35 (2H, d, J=8.4 Hz),7.52 (2H, d, J=8.4 Hz), 7.53 (1H, m), 7.7 (1H, br), 8.02 (1H, m), 8.49(1H, d, J=2.4 Hz).

IR (ATR) cm⁻¹: 1583, 1487, 1321, 1149, 827, 725.

mp: 113-114° C.

MS m/z: 477 (M⁺+H).

Anal. calcd for C₂₄H₂₃ClF₂N₂O₂S: C, 60.44%; H, 4.86%; N, 5.87%; S,6.72%; Cl, 7.43%; F, 7.97%. Found: C, 59.87%; H, 4.81%; N, 5.83%; S,6.87%; Cl, 7.55%; F, 8.02%.

Example 3374-[[6-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]morpholine

To a methylene chloride solution (5 ml) of the[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde(82 mg, 0.2 mmol) obtained in Example 335 and morpholine (35 μl, 0.4mmol) were added acetic acid (23 μl, 0.4 mmol) and sodiumtriacetoxyborohydride (85 mg, 0.4 mmol) at room temperature. Theresulting mixture was stirred for 3 hours. After a saturated aqueoussolution of sodium bicarbonate was added to quench the reaction, ethylacetate (80 ml) was added to dilute the reaction mixture. The organiclayer obtained by separation was washed with water and brine, dried andconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel chromatography (hexane:ethyl acetate=1:1),followed by crystallization from ethanol to yield the title compound (90mg, 94%).

¹H-NMR (400 MHz, CDCl₃) δ: 2.4 (4H, m), 3.49 (2H, s), 3.6 (4H, m), 5.92(1H, s), 6.90 (1H, m), 6.98 (1H, m), 7.36 (2H, d, J=8.4 Hz), 7.53 (2H,d, J=8.4 Hz), 7.57 (1H, d, J=8.0 Hz), 7.71 (1H, br-d, J=8.0 Hz), 8.02(1H, m), 8.53 (1H, d, J=2.0 Hz).

IR (ATR) cm⁻¹: 1583, 1484, 1321, 1149, 1116, 827, 725.

mp: 120-121° C.

MS m/z: 479 (M⁺+H).

Anal. calcd for C₂₂H₂₁ClF₂N₂O₃S: C, 57.68%; H, 4.42%; N, 5.85%; S,6.70%; Cl, 7.40%; F, 7.93%. Found: C, 57.41%; H, 4.43%; N, 5.90%; S,6.82%; Cl, 7.52%; F, 7.91%.

Example 338[6-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid

To a t-butanol solution (3.0 ml) of the[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde(110 mg, 0.27 mmol) obtained in Example 335 was added 2-methyl-2-butene(143 μl, 1.35 mmol). An aqueous solution (0.6 ml) of sodium dihydrogenphosphate (32.4 mg, 0.27 mmol), and sodium chlorite (98 mg, 1.08 mmol)were added successively to the resulting suspension and the mixture wasstirred for 2 hours. To the reaction mixture were added water (30 ml)and acetic acid (1 ml). The mixture was extracted with ethyl acetate(100 ml). The extract was washed with brine, dried and distilled underreduced pressure. The residue thus obtained was crystallized fromethanol, whereby the title compound (71 mg, 62%) was obtained ascolorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 6.03 (1H, s), 6.96 (1H, m), 7.03 (1H, m),7.42 (2H, d, J=8.4 Hz), 7.56 (2H, d, J=8.4 Hz), 7.73 (1H, d, J=8.4 Hz),7.97 (1H, m), 8.35 (1H, dd, J=2.0, 8.4 Hz), 9.20 (1H, d, J=2.0 Hz).

IR (ATR) cm⁻¹: 1685, 1596, 1498, 1322, 1153, 1085, 754.

mp: >230° C.

MS m/z: 424 (M⁺+H).

Anal. calcd for C₁₉H₁₂ClF₂NO₄S: C, 53.84%; H, 2.85%; N, 3.30%; S, 7.57%;Cl, 8.37%; F, 8.97%. Found: C, 53.47%; H, 2.81%; N, 3.46%; S, 7.65%; Cl,8.49%; F, 9.00%.

Example 3393-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-N-oxide

To a methylene chloride solution (15 ml) of the3-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine (162 mg,0.427 mmol) obtained in Example 141 was added 3-chloroperbenzoic acid(81 mg, 0.47 mmol) and the mixture was stirred for 24 hours. Thereaction mixture was diluted with ether (60 ml), followed by washingwith a saturated aqueous solution of sodium bicarbonate, water andbrine. After drying, the solution was filtered and the filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to silica gel chromatography (ethyl acetate), whereby thetitle compound (68 mg, 40%) was obtained. The compound was crystallizedfrom ethanol and was obtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 5.58 (1H, s), 6.95 (1H, m), 7.03 (1H, m),7.29 (1H, dd, J=6.6, 8.0 Hz), 7.42 (2H, d, J=8.6 Hz), 7.57 (1H, d, J=8.0Hz), 7.62 (2H, d, J=8.4 Hz), 7.66 (1H, m), 8.10 (1H, d, J=6.6 Hz), 8.29(1H, s).

IR (ATR) cm⁻¹: 1573, 1492, 1438, 1329, 1248, 1151, 1081, 820.

mp: 183-184° C.

MS m/z: 396 (M⁺+H).

Anal. calcd for C₁₈H₁₂ClF₂NO₃S: C, 54.62%; H, 3.06%; N, 3.54%; S, 8.10%;Cl, 8.96%; F, 9.60%. Found: C, 54.19%; H, 2.99%; N, 3.67%; S, 8.27%; Cl,8.92%; F, 9.53%.

Example 3404-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-N-oxide

To a methylene chloride solution (20 ml) of the4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine (221 mg,0.58 mmol) obtained in Example 142 was added 3-chloroperbenzoic acid(100 mg, 0.58 mmol) and the mixture was stirred for 20 hours. Thereaction mixture was diluted with ether (60 ml), followed by washingwith a saturated aqueous solution of sodium bicarbonate, water andbrine. The solution was dried and then filtered. The filtrate was thenconcentrated under reduced pressure. The residue thus obtained wassubjected to silica gel chromatography (ethyl acetate) to yield thetitle compound (183 mg, 80%). The compound was then crystallized fromethanol and obtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 5.62 (1H, s), 6.97 (1H, m), 7.06 (1H, m),7.42 (2H, d, J=7.2 Hz), 7.44 (2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hz),7.68 (1H, m), 8.17 (2H, d, J=7.2 Hz).

IR (ATR) cm⁻¹: 1479, 1322, 1263, 1149, 1081, 813.

mp: 211-212° C.

MS m/z: 396 (M⁺+H).

Anal. calcd for C₁₈H₁₂ClF₂NO₃S: C, 54.62%; H, 3.06%; N, 3.54%; S, 8.10%;Cl, 8.96%; F, 9.60%. Found: C, 54.19%; H, 2.92%; N, 3.65%; S, 8.26%; Cl,8.99%; F, 9.61%.

Referential Example 483-Chloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine

To a tetrahydrofuran solution (14 ml) of diisopropylamine (1.4 ml, 10mmol) was added n-butyl lithium (6.3 ml, 1.59M hexane solution) at −78°C. and the mixture was stirred for 10 minutes. Then, 3-chloropyridine(1.13 g, 10 mmol) was added to the resulting mixture. Thirty minuteslater, 2,5-difluorobenzaldehyde (1.09 ml, 10 mmol) was added to themixture. The mixture was warmed gradually to 0° C., at which stirringwas conducted for further 10 minutes. An aqueous solution of ammoniumchloride was added and the mixture was diluted with ethyl acetate (80ml). The organic layer obtained by separation was washed with brine andthen dried. After filtration, the filtrate was concentrated underreduced pressure. The precipitate thus obtained was triturated withethanol to yield the title compound (1.33 g, 52%).

¹H-NMR (400 MHz, CDCl₃) δ: 4.87 (1H, br), 6.26 (1H, s), 6.90-7.02 (3H,m), 7.58 (1H, d, J=4.8 Hz), 8.47 (1H, s), 8.48 (1H, d, J=4.8 Hz).

IR (ATR) cm⁻¹: 3178, 1592, 1490, 1174, 1039.

mp: 169-170° C.

MS m/z: 255 (M⁺).

Referential Example 492,5-Dichloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine

To a tetrahydrofuran solution (14 ml) of diisopropylamine (1.4 ml, 10mmol) was added n-butyl lithium (6.3 ml, 1.59M hexane solution) at −78°C. After stirring for 10 minutes, 2,5-dichloropyridine (1.48 g, 10 mmol)was added. Thirty minutes later, 2,5-difluorobenzaldehyde (1.09 ml, 10mmol) was added to the mixture. The resulting mixture was warmedgradually to 0° C. and stirring was conducted for further 10 minutes. Anaqueous solution of ammonium chloride was added and the mixture wasdiluted with ethyl acetate (80 ml). The organic layer was separated,washed with brine and dried. After filtration, the filtrate wasconcentrated under reduced pressure. The precipitate thus obtained wastriturated with ethanol to yield the title compound (1.93 g, 67%).

¹H-NMR (400 MHz, CDCl₃) δ: 2.64 (1H, d, J=4.0 Hz), 6.28 (1H, d, J=4.0Hz), 6.89 (1H, m), 7.02 (2H, m), 7.64 (1H, s), 8.30 (1H, s).

IR (ATR) cm⁻¹: 3226, 1579, 1492, 1243, 1110, 1062.

mp: 160-161° C.

MS m/z: 289 (M⁺).

Example 3413-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine

After 3-chloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (511 mg,2.0 mmol) which had been obtained in Referential Example 48 wasdissolved in thionyl chloride (3.0 ml), a catalytic amount ofdimethylformamide was added thereto. The resulting mixture was stirredfor 17 hours. The reaction mixture was concentrated under reducedpressure. Toluene was added to the residue and the mixture wasconcentrated further.

The residue was dissolved in dimethylformamide (10 ml), followed by theaddition of 4-chlorobenzenethiol (375 mg, 2.6 mmol) and potassiumcarbonate (414 mg, 3 mmol) under nitrogen atmosphere. The resultingmixture was stirred at 60° C. for 3 hours. After the reaction mixturewas cooled to room temperature, diethyl ether (60 ml) was added. Themixture was washed with water and brine. The organic layer was driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue was subjected to silica gel chromatography (hexane:ethylacetate=8:1), whereby the title compound (196 mg, 26%) was obtained as asolid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.07 (1H, s), 6.95-7.08 (2H, m), 7.18 (1H,m), 7.23 (2H, d, J=8.8 Hz), 7.26 (2H, d, J=8.8 Hz), 7.58 (1H, d, J=5.2Hz), 8.51 (1H, d, J=5.2 Hz), 8.58 (1H, s).

IR (ATR) cm⁻¹: 1577, 1473, 1211, 1089, 1012, 817.

mp: 70-72° C.

MS m/z: 382 (M⁺+1).

Example 3422,5-Dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine

After the 2,5-dichloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine(580 mg, 2.0 mmol) obtained in Referential Example 49 was dissolved inthionyl chloride (3.0 ml), a catalytic amount of dimethylformamide wasadded and the resulting mixture was stirred for 17 hours. The reactionmixture was concentrated under reduced pressure. Toluene was added tothe residue and the mixture was concentrated further.

The residue was dissolved in dimethylformamide (10 ml), followed by theaddition of 4-chlorobenzenethiol (375 mg, 2.6 mmol) and potassiumcarbonate (414 mg, 3 mmol) under nitrogen atmosphere. The mixture wasstirred at 50° C. for 17 hours. After cooling to room temperature,diethyl ether (60 ml) was added to the mixture. The mixture was washedwith water and brine. The organic layer was dried over magnesiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel chromatography (hexane:ether=10:1), whereby thetitle compound (484 mg, 58%) was obtained as a solid.

¹H-NMR (400 MHz, CDCl₃) δ: 5.96 (1H, s), 6.95-7.04 (2H, m), 7.01 (1H,m), 7.23 (2H, d, J=8.8 Hz), 7.26 (2H, d, J=8.8 Hz), 7.54 (1H, s), 8.33(1H, s)

IR (ATR) cm⁻¹: 1570, 1495, 1473, 1326, 1207, 1090, 1012, 816.

mp: 128-129° C.

MS m/z: 416 (M⁺+1).

Example 3433-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine

Hexaammonium heptamolybdate tetrahydrate (60 mg) and a 30% aqueoushydrogen peroxide solution (6 ml) were successively added to a solutionof the3-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(122 mg, 0.32 mmol), which had been obtained in Example 341, in methanol(12 ml). The resulting mixture was stirred for 24 hours. The reactionmixture was diluted with ethyl acetate. The solution was washed withwater and brine, and concentrated under reduced pressure. The residuewas crystallized from ethanol, whereby the title compound (103 mg, 78%)was obtained as colorless needle crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 6.23 (1H, s), 6.94 (1H, m), 7.06 (1H, m),7.41 (2H, d, J=8.0 Hz), 7.53 (1H, m), 7.59 (2H, d, J=8.0 Hz), 8.11 (1H,d, J=5.2 Hz), 8.55 (1H, s), 8.60 (1H, d, J=5.2 Hz).

IR (ATR) cm⁻¹: 1577, 1490, 1321, 1311, 1151, 1083, 821.

mp: 160-161° C.

MS m/z: 414 (M⁺+H).

Anal. calcd for C₁₈H₁₁Cl₂F₂NO₂S: C, 52.19%; H, 2.68%; N, 3.38%; S,7.74%; Cl, 17.12%; F, 9.17%. Found: C, 52.17%; H, 2.69%; N, 3.44%; S,7.96%; Cl, 17.12%; F, 9.00%.

Example 3443-Chloro-4-[(4-chlorophenylsulfinyl)-(2,5-difluorophenyl)methyl]pyridine

After 3-chloroperbenzoic acid (33 mg, 0.20 mmol) was added to a solutionof the3-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (75mg, 0.20 mmol), which had been obtained in Example 341, in methylenechloride (10 ml), the mixture was stirred for 3 hours under ice cooling.The reaction mixture was diluted with ether (80 ml). The solution waswashed with water and brine, and then concentrated under reducedpressure. The residue was purified by silica gel chromatography(hexane:ethyl acetate=3:1), whereby the title compound (48 mg, 60%) wasobtained as a diastereomeric mixture (1:1).

¹H-NMR (400 MHz, CDCl₃) δ: 5.53 (½H, s), 5.66 (½H, s), 6.83 (½H, s),6.95-7.08 ( 3/2H, m), 7.23 (½H, m), 7.25 (1H, d, J=8.4 Hz), 7.26 (1H, d,J=8.4 Hz), 7.34 (1H, d, J=8.4 Hz), 7.36 (1H, d, J=8.4 Hz), 7.37 (½H, m),7.76 (½H, d, J=5.2 Hz), 7.98 (½H, d, J=5.2 Hz), 8.47 (½H, s), 8.56 (½H,d, J=5.2 Hz), 8.60 (½H, s), 8.61 (½H, d, J=5.2 Hz).

IR (ATR) cm⁻¹: 1577, 1490, 1396, 1168, 1049, 1033, 817.

MS m/z: 398 (M⁺+H).

FAB-MS: 397.9992 (Calcd for C₁₈H₁₂Cl₂F₂NOS: 397.9985).

Example 3452,5-Dichloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine0.5 hydrate

After 3-chloroperbenzoic acid (62 mg, 0.36 mmol) was added to a solutionof the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(60 mg, 0.14 mmol), which had been obtained in Example 342, in methylenechloride (3.0 ml), the mixture was stirred at room temperature for 3hours. The reaction mixture was diluted with ether (80 ml). The solutionwas washed with a saturated aqueous solution of sodium bicarbonate andbrine, and then, concentrated under reduced pressure. The residue waspurified by silica gel chromatography (hexane:ethyl acetate=5:1) andcrystallized from hexane to yield the title compound (55 mg, 88%).

¹H-NMR (400 MHz, CDCl₃) δ: 6.15 (1H, s), 6.93 (1H, m), 7.05 (1H, m),7.44 (2H, d, J=8.8 Hz), 7.50 (1H, m), 7.59 (2H, d, J=8.8 Hz), 8.13 (1H,s), 8.55 (1H, s), 8.33 (1H, s). IR (ATR) cm⁻¹: 1569, 1492, 1321, 1147,1118, 1083, 821.

mp: 147-148° C.

MS m/z: 448 (M⁺+H).

Anal. calcd for C₁₈H₁₁Cl₃F₂NO₂S.0.5H₂O: C, 47.23%; H, 2.42%; N, 3.06%;S, 7.01%; Cl, 23.24%; F, 8.30%. Found: C, 47.25%; H, 2.24%; N, 3.21%; S,7.19%; Cl, 23.25%; F, 8.32%.

FAB-MS: 447.9572 (Calcd for C₁₈H₁₁Cl₃F₂NO₂S: 447.9544).

Example 3464-[5-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholine

A solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(100 mg, 0.24 mmol) obtained in Example 342 and morpholine (200 μl) in1,4-dioxane (1.0 ml) was stirred under nitrogen atmosphere at 100° C.for 2 days. The reaction mixture was cooled to room temperature. Afterdilution with ethyl acetate (40 ml), the solution was washed with waterand brine, dried and concentrated under reduced pressure. The residuethus obtained was purified by silica gel chromatography (hexane:ethylacetate=5:1) to yield the title compound (100 mg, 89%) as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 3.48 (4H, m), 3.82 (4H, m), 6.00 (1H, s),6.94 (1H, s), 6.94-7.04 (2H, m), 7.09 (1H, m), 7.23 (2H, d, J=8.4 Hz),7.24 (2H, d, J=8.4 Hz), 8.12 (1H,

MS m/z: 467 (M⁺+H)

Example 3474-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholine

To a solution of4-[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholine(90 mg, 0.19 mmol) in methanol (12 ml) was added hexaammoniumheptamolybdate tetrahydrate (60 mg), followed by the addition of a 30%aqueous hydrogen peroxide solution (6 ml). The resulting mixture wasstirred for 8 hours. After dilution with ethyl acetate, the solution waswashed with water and brine and then, concentrated under reducedpressure. The residue was subjected to silica gel chromatography(hexane:ethyl acetate=3:1) and then, crystallized from ethanol, wherebythe title compound (80 mg, 83%) was obtained as colorless needlecrystals.

¹H-NMR (400 MHz, CDCl₃) δ: 3.54 (4H, m), 3.84 (4H, m), 6.12 (1H, s),6.90 (1H, m), 7.02 (1H, m), 7.42 (2H, d, J=8.4 Hz), 7.45 (1H, s), 7.46(1H, m), 7.58 (2H, d, J=8.4 Hz), 8.06 (1H, s).

IR (ATR) cm⁻¹: 1585, 1494, 1475, 1317, 1240, 1145, 1091, 831.

mp: 180-181° C.

MS m/z: 499 (M⁺+H)

Anal. calcd for C₂₂H₁₈Cl₂F₂N₂O₃S: C, 52.92%; H, 3.63%; N, 5.61%; S,6.42%; Cl, 14.20%; F, 7.61%. Found: C, 52.68%; H, 3.56%; N, 5.69%; S,6.70%; Cl, 14.32%; F, 7.97%

Example 3484-[2-[5-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]aminoethyl]morpholine

Under nitrogen atmosphere, a solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(100 mg, 0.24 mmol) obtained in Example 342 and 4-morpholine ethylamine(200 μl) in 1,4-dioxane (1.0 ml) was stirred at 100° C. for 2 days.After cooling to room temperature, the reaction mixture was diluted withethyl acetate (40 ml). The solution was washed with water and brine,dried and then concentrated under reduced pressure. The residue thusobtained was purified by silica gel chromatography (3%methanol/chloroform), whereby the title compound (12 mg, 10%) wasobtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 2.42 (4H, m), 2.54 (2H, d, J=6.0 Hz), 3.27(2H, q, J=6.0 Hz), 3.67 (4H, m), 5.12 (br, 1H), 5.90 (1H, s), 6.61 (1H,s), 6.86-7.0 (2H, m), 7.06 (1H, m), 7.15 (2H, d, J=8.4 Hz), 7.16 (2H, d,J=8.4 Hz), 7.95 (1H, s).

MS m/z: 510 (M⁺+H).

Example 3494-[2-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]aminoethyl]morpholineN-oxide

To a solution of4-[2-[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]aminoethyl]morpholine(11 mg, 0.032 mmol) in methanol (12 ml) was added hexaammoniumheptamolybdate tetrahydrate (10 mg). A 30% aqueous hydrogen peroxidesolution (1 ml) was added to the resulting mixture, followed by stirringfor 8 hours. The reaction mixture was diluted with ethyl acetate. Thesolution was washed with water and brine. After the solution wasconcentrated under reduced pressure, the residue was purified by silicagel chromatography (3% methanol, 3% t-butylamine/chloroform solution),whereby the title compound (5.0 mg, 42%) was obtained.

¹H-NMR (400 MHz, CDCl₃) δ: 3.2-3.4 (4H, m), 3.54 (2H, m), 3.81 (2H, m),3.91 (2H, m), 4.44 (2H, m), 6.09 (1H, s), 6.88 (1H, m), 6.98 (1H, m),7.22 (1H, s), 7.40 (2H, d, J=8.4 Hz), 7.51 (1H, m), 7.60 (2H, d, J=8.4Hz), 7.94 (1H, s).

IR (ATR) cm⁻¹: 1600, 1494, 1324, 1151, 1085, 754.

MS m/z: 558 (M⁺+H).

FAB-MS: 558.0837 (Calcd for C₂₄H₂₄Cl₂F₂N₃O₄S: 558.0833).

Example 3505-Azidomethyl-2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine

In a mixture of carbon tetrachloride (4 ml) and N,N-dimethylformamide(16 ml) was dissolved the2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-(hydroxymethyl)pyridine(471 mg, 1.15 mmol) obtained in Example 331. Sodium azide (112 mg, 1.72mmol) and triphenylphosphine (451 mg, 1.72 mmol) were added and themixture was stirred at 90° C. for 3 hours. Water was added to thereaction mixture, followed by extraction with ethyl acetate. The organiclayer was then washed successively with water and brine, dried oversodium sulfate and concentrated under reduced pressure. The residue thusobtained was subjected to chromatography on a silica gel column. Afraction obtained from the elution portion with hexane:ethyl acetate=3:1was concentrated under reduced pressure, whereby the title compound (244mg, 0.561 mmol, 49%) was obtained as a colorless amorphous substance.

¹H-NMR (400 MHz, CDCl₃) δ: 4.42 (2H, s), 5.96 (1H, s), 6.94 (1H, m),6.99-7.05 (1H, m), 7.40 (2H, d, J=8.8 Hz), 7.55 (2H, d, J=8.8 Hz), 7.60(1H, d, J=8.1 Hz), 7.72 (1H, dd, J=8.1, 2.0 Hz), 8.02 (1H, m), 8.57 (1H,d, J=2.0 Hz).

MS m/z: 435 (M⁺+H).

Example 351[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine

Under argon atmosphere,5-azidomethyl-2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine(77 mg, 0.177 mmol), palladium on carbon (14 mg), and ethyl acetate (2ml) were added to ethanol (10 ml). The resulting mixture was stirred for50 minutes under 1 atom hydrogen atmosphere. After filtration, thefiltrate was concentrated under reduced pressure. The residue thusobtained was subjected to chromatography on a silica gel column. Afraction obtained from the elution portion withdichloromethane:methanol=10:1 was concentrated under reduced pressure,whereby the title compound (28 mg, 0.0685 mmol, 39%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.84 (2H, brs), 3.92 (2H, s), 5.94 (1H, s),6.92 (1H, m), 7.03-6.98 (1H, m), 7.39 (2H, d, J=8.3 Hz), 7.56 (2H, d,J=8.3 Hz), 7.60 (1H, d, J=8.1 Hz), 7.74 (1H, d, J=8.1 Hz), 8.01 (1H, m),8.57 (1H, s).

MS m/z: 409 (M⁺+H).

Example 352 tert-Butyl[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]carbamate

The5-azidomethyl-2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine(230 mg, 0.529 mmol) obtained in Example 350 and palladium on carbon (46mg) were added to a mixture of ethyl acetate (15 ml) and ethanol (15ml). The resulting mixture was stirred for 45 minutes under 1 atomhydrogen atmosphere. After filtration, the filtrate was concentratedunder reduced pressure. The residue thus obtained was dissolved indichloromethane (5 ml). Triethylamine (70 μl, 0.499 mmol) anddi-tert-butyl carbonate (174 mg, 0.996 mmol) were added to the resultingsolution. The mixture was stirred at room temperature for 3 days. Thereaction mixture was concentrated under reduced pressure. The residuethus obtained was subjected to flash chromatography on a silica gelcolumn. A fraction obtained from the elution portion with hexane:ethylacetate=4:1 was concentrated under reduced pressure, whereby titlecompound (78 mg, 0.153 mmol, 37%) was obtained as a colorless amorphoussubstance.

¹H-NMR (400 MHz, CDCl₃) δ: 1.45 (9H, s), 4.34 (2H, d, J=5.6 Hz), 4.91(1H, brs), 5.93 (1H, s), 6.91 (1H, m), 6.98-7.04 (1H, m), 7.39 (2H, d,J=8.8 Hz), 7.54 (2H, d, J=8.8 Hz), 7.59 (1H, d, J=7.8 Hz), 7.67 (1H, dd,J=7.8, 2.2 Hz), 7.99 (1H, m), 8.53 (1H, d, J=2.2 Hz).

IR (ATR) cm⁻¹: 1700, 1573, 1492, 1394, 1365, 1322, 1276, 1241, 1149,1087, 1047, 1014.

MS m/z: 509 (M⁺+H).

Example 353 tert-Butyl[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-N-(tert-butoxycarbonyl)carbamate

Under nitrogen atmosphere, diisopropyl azodicarboxylate (128 l, 0.653mmol) was added to a solution of the2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-(hydroxymethyl)pyridine(178 mg, 0.435 mmol) obtained in Example 331, di-tert-butyliminodicarboxylate (142 mg, 0.653 mmol) and triphenylphosphine (171 mg,0.653 mmol) in tetrahydrofuran (5 ml) and the resulting mixture wasstirred at room temperature for 5 hours. Water was added to the reactionmixture, followed by extraction with ethyl acetate. The organic layerwas then washed successively with water and brine. The organic layerthus obtained was dried over sodium sulfate and concentrated underreduced pressure. The residue thus obtained was subjected to flashchromatography on a silica gel column. A fraction obtained from theelution portion with hexane:ethyl acetate=4:1 was concentrated underreduced pressure, whereby the title compound (78 mg, 0.128 mmol, 32%)was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.48 (18H, s), 4.78 (2H, s), 5.94 (1H, s),6.93 (1H, td, J=9.0, 4.4 Hz), 6.98-7.04 (1H, m), 7.38 (2H, d, J=8.6 Hz),7.56 (2H, d, J=8.6 Hz), 7.58 (1H, d, J=8.1 Hz), 7.71 (1H, dd, J=8.1, 2.4Hz), 7.96-8.00 (1H, m), 8.57 (1H, d, J=2.4 Hz).

IR (ATR) cm⁻¹: 2979, 1795, 1727, 1695, 1492, 1392, 1367, 1328, 1255,1224, 1132, 1087, 1033.

MS m/z: 609 (M⁺+H).

Example 3546-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylaminehydrochloride

Concentrated hydrochloric acid (2 ml) was added to a solution oftert-butyl[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-N-(tert-butoxycarbonyl)carbamate(70 mg, 0.115 mmol) in ethanol (2 ml) and the mixture was stirred atroom temperature for 3 hours. The reaction mixture was concentratedunder reduced pressure. Ethanol was added to the residue and the mixturewas concentrated under reduced pressure, whereby the title compound (51mg, 0.115 mmol, 100%) was obtained as a white powder.

¹H-NMR (400 MHz, CD₃OD) δ: 4.18 (2H, s), 6.22 (1H, s), 7.03 (1H, td,J=9.3, 4.4 Hz), 7.11-7.17 (1H, m), 7.52 (2H, d, J=8.8 Hz), 7.64 (2H, d,J=8.8 Hz), 7.79 (1H, d, J=8.3 Hz), 7.92 (1H, dd, J=8.3, 2.2 Hz),8.05-8.09 (1H, m), 8.71 (1H, d, J=2.2 Hz).

IR (ATR) cm⁻¹: 1600, 1571, 1492, 1394, 1349, 1313, 1278, 1232, 1170,1147, 1079, 1037, 1012.

MS (m/z): 409 (M⁺+H).

Anal. calcd for C₂₀H₁₅ClF₂N₂O₂S.HCl: C, 51.25; H, 3.62; Cl, 15.92; F,8.53; N, 6.29. Found: C, 51.11; H, 3.57; Cl, 15.50; F, 8.39; N, 5.83.

Example 355N-Acetyl-N-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]acetamide(Compound A) andN-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]acetamide(Compound B)

Compound A Compound B

Under ice cooling, N-methylmorpholine (26 l, 0.234 mmol) and acetylchloride (16 l, 0.234 mmol) were added to a solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(40 mg, 0.0978 mmol), which had been obtained in Example 351, indichloromethane (3 ml). The resulting mixture was stirred at roomtemperature for 16 hours. Water was added to the reaction mixture,followed by extraction with ethyl acetate. The organic layer was washedsuccessively with water and brine, dried over sodium sulfate andconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column. A fraction obtained from theelution portion with hexane:ethyl acetate=2:3 was concentrated underreduced pressure, whereby the title compound A (low polarity compound)(15 mg, 0.0304 mmol, 40%) was obtained as a white powder and the titlecompound B (high polarity compound) (12 mg, 0.0266 mmol, 27%) wasobtained as a white powder.

Compound A

¹H-NMR (400 MHz, CDCl₃) δ: 2.43 (6H, s), 4.96 (2H, s), 5.93 (1H, s),6.91 (1H, m), 6.98-7.03 (1H, m), 7.39 (2H, d, J=8.5 Hz), 7.54-7.61 (2H,m), 7.55 (2H, d, J=8.5 Hz), 8.02 (1H, m), 8.51 (1H, d, J=1.7 Hz). IR(ATR) cm⁻¹: 1712, 1689, 1573, 1492, 1423, 1369, 1319, 1267, 1201, 1149,1079, 1029.

mp: 60-64° C.

MS m/z: 493 (M⁺+H).

Compound B

¹H-NMR (400 MHz, CDCl₃) δ: 2.03 and 2.04 (3H, rotamers), 4.42-4.50 (2H,m), 5.89 (1H, brs), 5.93 (1H, s), 6.92 (1H, td, J=9.1, 4.4 Hz),6.97-7.02 (1H, m), 7.41 (2H, d, J=8.1 Hz), 7.57 (2H, d, J=8.1 Hz), 7.61(1H, d, J=8.1 Hz), 7.71 (1H, d, J=8.1 Hz), 7.98-8.03 (1H, m), 8.54 (1H,s).

IR (ATR) cm⁻¹: 1650, 1673, 1525, 1486, 1430, 1396, 1355, 1319, 1280,1230, 1147, 1085, 1016.

mp: 177-178° C.

MS m/z: 451 (M⁺+H).

Example 356N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-N′,N′-dimethylsulfamide

To a solution of the6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylaminehydrochloride (60 mg, 0.135 mmol) in dichloromethane (5 ml) were addedN-methylmorpholine (180 l, 1.62 mmol), 4-dimethylaminopyridine (10 mg,0.0819 mmol) and N,N-dimethylsulfamoyl chloride (66 l, 0.609 mmol). Theresulting mixture was stirred at room temperature for 24 hours. Waterwas added to the reaction mixture, followed by extraction withdichloromethane. The organic layer was washed successively with asaturated aqueous solution of sodium bicarbonate and brine. Theresulting organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue thus obtained wassubjected to flash chromatography on a silica gel column. A fractionobtained from the elution portion with hexane:ethyl acetate=3:2 wasconcentrated under reduced pressure, whereby the title compound (48 mg,0.0930 mmol, 70%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.76 (6H, s), 4.29 (2H, d, J=6.4 Hz), 4.43(1H, t, J=6.4 Hz), 5.94 (1H, s), 6.92 (1H, m), 6.98-7.04 (1H, m), 7.41(2H, d, J=8.6 Hz), 7.58 (2H, d, J=8.6 Hz), 7.66 (1H, d, J=8.1 Hz), 7.79(1H, dd, J=8.1, 2.5 Hz), 8.02 (1H, m), 8.61 (1H, d, J=2.5 Hz).

mp: 177-178° C.

MS m/z: 516 (M⁺+H).

Example 357 Ethyl2-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamino]-2-oxoacetate

Under ice cooling, N-methylmorpholine (10 l, 0.0881 mmol) and ethylchloroglyoxylate (9 l, 0.0807 mmol) were added to the6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(30 mg, 0.0734 mmol), which had been obtained in Example 351, indichloromethane (4 ml). The resulting mixture was stirred at roomtemperature for 1 hour. Water was added to the reaction mixture,followed by extraction with dichloromethane. The organic layer was thenwashed successively with a saturated aqueous solution of sodiumbicarbonate and brine, dried over magnesium sulfate and concentratedunder reduced pressure. The residue thus obtained was subjected to flashchromatography on a silica gel column. A fraction obtained from theelution portion with hexane:ethyl acetate=3:2 was concentrated underreduced pressure, whereby the title compound (28 mg, 0.0550 mmol, 76%)was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 1.39 (3H, t, J=7.1 Hz), 4.37 (2H, q, J=7.1Hz), 4.55 (2H, d, J=5.9 Hz), 5.94 (1H, s), 6.89-6.94 (1H, m), 6.98-7.05(1H, m), 7.40 (2H, d, J=8.3 Hz), 7.56 (2H, d, J=8.3 Hz), 7.53 (1H, brs),7.62 (1H, d, J=8.1 Hz), 7.72 (1H, d, J=8.1 Hz), 7.97-8.03 (1H, m), 8.58(1H, s).

mp: 193-194° C.

MS m/z: 509 (M⁺+H).

Example 358N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-2-(4-methylphenylsulfonylamino)acetamide

Triethylamine (45 l, 0.324 mmol), 4-dimethylaminopyridine (5 mg, 0.0449mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21mg, 0.108 mmol) and N-p-tosylglycine (25 mg, 0.108 mmol) were added to asolution of the6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylaminehydrochloride (40 mg, 0.0898 mmol), which had been obtained in Example354, in dichloromethane (6 ml). The resulting mixture was stirred atroom temperature for 16 hours. The reaction mixture was diluted withdichloromethane, followed by successive washing with water, a saturatedaqueous solution of sodium bicarbonate and brine. The organic layer thusobtained was dried over magnesium sulfate and concentrated under reducedpressure. The residue thus obtained was subjected to flashchromatography on a silica gel column. A fraction obtained from theelution portion with hexane:ethyl acetate=2.3 was concentrated underreduced pressure, whereby the title compound (41 mg, 0.0661 mmol, 73%)was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.44 (3H, s), 3.59 (2H, d, J=6.4 Hz), 4.44(2H, dd, J=6.1, 2.8 Hz), 5.42 (1H, t, J=6.1 Hz), 5.95 (1H, s), 6.91 (1H,m), 6.96-7.03 (2H, m), 7.33 (2H, d, J=8.3 Hz), 7.41 (2H, d, J=8.6 Hz),7.57 (2H, d, J=8.6 Hz), 7.58 (1H, d, J=8.1 Hz), 7.66 (1H, dd, J=8.1, 2.4Hz), 7.74 (2H, d, J=8.3 Hz), 8.01 (1H, m), 8.49 (1H, d, J=2.4 Hz)

mp: 217-218° C.

MS m/z: 620 (M⁺+H).

Example 359N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-2-dimethylaminoacetamide

Triethylamine (12 l, 0.0881 mmol), 4-dimethylaminopyridine (5 mg, 0.0367mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17mg, 0.0881 mmol) and N,N-dimethylglycine (9 mg, 0.0881 mmol) were addedto a solution of the6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(30 mg, 0.0734 mmol), which had been obtained in Example 351, indichloromethane (5 ml). The resulting mixture was stirred at roomtemperature for 14 hours. The reaction mixture was diluted withdichloromethane, followed by successive washing with water, a saturatedaqueous solution of sodium bicarbonate and brine. The organic layer thusobtained was dried over magnesium sulfate and concentrated under reducedpressure. The residue was subjected to flash chromatography on a silicagel column. A fraction obtained from the elution portion withhexane:ethyl acetate=1:4 was concentrated under reduced pressure,whereby the title compound (21 mg, 0.0425 mmol, 58%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.30 (6H, s), 3.01 (2H, s), 4.50 (2H, d,J=6.1 Hz), 5.93 (1H, s), 6.91 (1H, m), 6.98-7.04 (1H, m), 7.40 (2H, d,J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz), 7.60 (1H, d, J=8.1 Hz), 7.62 (1H,brs), 7.69 (1H, dd, J=8.1, 2.4 Hz), 8.02 (1H, m), 8.56 (1H, d, J=2.4Hz).

mp: 177-179° C.

MS m/z: 494 (M⁺+H).

Example 360N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-4-(formylmethylamino)benzamide

Triethylamine (21 l, 0.147 mmol), 4-dimethylaminopyridine (7 mg, 0.0610mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28mg, 0.147 mmol) and N-formyl-4-(methylamino)benzoic acid (26 mg, 0.147mmol) were added to a solution of the6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(50 mg, 0.122 mmol), which had been obtained in Example 351, indichloromethane (5 ml). The resulting mixture was stirred at roomtemperature for 2 hours. The reaction mixture was diluted withdichloromethane, followed by successive washing with water, a saturatedaqueous solution of sodium bicarbonate and brine. The organic layer wasdried over magnesium sulfate and concentrated under reduced pressure.The residue thus obtained was subjected to flash chromatography on asilica gel column. A fraction obtained from the elution portion withhexane:ethyl acetate=3:7 was concentrated under reduced pressure,whereby the title compound (60 mg, 0.105 mmol, 87%) was obtained as acolorless amorphous substance.

¹H-NMR (400 MHz, CDCl₃) δ: 3.35 (3H, s), 4.67-4.71 (2H, m), 5.94 (1H,s), 6.53 (1H, brs), 6.90 (1H, m), 6.97-7.03 (1H, m), 7.25 (2H, d, J=8.6Hz), 7.40 (2H, d, J=8.6 Hz), 7.56 (2H, d, J=8.6 Hz), 7.63 (1H, d, J=8.1Hz), 7.78 (1H, dd, J=8.1, 2.2 Hz), 7.86 (2H, d, J=8.6 Hz), 8.03 (1H, m),8.61 (1H, s), 8.64 (1H, d, J=2.2 Hz).

MS m/z: 570 (M⁺+H).

Example 361N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-4-(methylthioformylamino)thiobenzamide

Under argon atmosphere, a lawesson's reagent (69 mg, 0.169 mmol) wasadded to a solution ofN-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-4-(formylmethylamino)benzamide(46 mg, 0.0807 mmol) in toluene (5 ml) and the mixture was heated underreflux for 12 hours. After cooling to room temperature, the reactionmixture was concentrated under reduced pressure. The residue thusobtained was subjected to flash chromatography on a silica gel column. Afraction obtained from the elution portion with hexane:ethyl acetate=4:1was concentrated under reduced pressure, whereby the title compound (40mg, 0.0664 mmol, 83%) was obtained as a yellow amorphous substance.

¹H-NMR (400 MHz, CDCl₃) δ: 3.72 (3H, s), 5.08 (2H, d, J=4.4 Hz), 5.92(1H, s), 6.89 (1H, td, J=9.0, 4.4 Hz), 6.98-7.05 (1H, m), 7.25 (2H, d,J=8.6 Hz), 7.40 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz), 7.60 (1H, d,J=8.1 Hz), 7.81 (1H, d, J=8.1 Hz), 7.87 (2H, d, J=8.6 Hz), 8.02-8.06(1H, m), 8.20 (1H, brs), 8.62 (1H, s), 9.70 (1H, s).

MS m/z: 602 (M⁺+H).

Example 362N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-2-(pyridin-3-yl)acetamide

The[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(30 mg, 0.073 mmol) obtained in Example 351, 3-pyridylacetic acidhydrochloride (16 mg, 0.092 mmol), 4-(dimethylamino)pyridine (5 mg, 0.04mmol) and triethylamine (0.025 ml, 0.18 mmol) were dissolved indichloromethane (5 ml). To the resulting solution was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17 mg,0.089 mmol). After stirring at room temperature for 14 hours, asaturated aqueous solution (0.1 ml) of sodium bicarbonate was added tothe reaction mixture. The residue obtained by concentration of thereaction mixture under reduced pressure was subjected to flash silicagel chromatography. A fraction obtained from the elution portion withdichloromethane:methanol=30:1 was concentrated under reduced pressure,whereby a white solid was obtained. The white solid was washed withether, whereby the title compound (35 mg, 0.066 mmol, 90%) was obtainedas a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 3.59 (2H, s), 4.45 (2H, dd, J=5.9, 1.5 Hz),5.92 (1H, s), 5.96-6.10 (1H, m), 6.86-6.98 (1H, m), 6.99-7.05 (1H, m),7.24-7.35 (1H, m), 7.39 (2H, d, J=8.8 Hz), 7.55-7.60 (3H, m), 7.60-7.71(2H, m), 7.96-8.06 (1H, m), 8.50 (2H, d, J=1.6 Hz), 8.55 (1H, d, J=4.8,1.6 Hz).

MS m/z: 528 (M⁺+H).

Example 363[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyldimethylcarbamate

To a solution of the2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-(hydroxylmethyl)pyridine(20 mg, 0.049 mmol), which had been obtained in Example 331, indichloromethane (0.3 ml) were added N-methylmorpholine (0.011 ml, 0.10mmol) and p-nitrophenyl chloroformate (15 mg, 0.074 mmol). The resultingmixture was stirred at room temperature for 30 minutes. At 0° C.,N-methylmorpholine (0.033 ml, 0.30 mmol) and then, p-nitrophenylchloroformate (15 mg, 0.074 mmol) were added further and the mixture wasstirred at room temperature for 30 minutes. Dimethylamine hydrochloride(20 mg, 0.25 mmol) was added to the mixture at 0° C. After stirring atroom temperature for 13 hours, the reaction mixture was washed with asaturated aqueous solution of ammonium chloride. The organic layer wasthen dried over anhydrous sodium sulfate. After filtration, the filtratewas concentrated under reduced pressure. The residue was subjected toflash silica gel chromatography. A fraction obtained from the elutionportion with hexane:ethyl acetate=7:3 was concentrated under reducedpressure. The resulting solid was washed with hexane and filtered,whereby the title compound (13 mg, 0.027 mmol, 55%) was obtained as awhite solid.

¹H-NMR (400 MHz, CDCl₃) δ: 2.94 (6H, s), 5.14 (2H, s), 5.94 (1H, s),6.87-7.07 (2H, m), 7.39 (2H, d, J=8.5 Hz), 7.55 (2H, d, J=8.5 Hz), 7.62(1H, d, J=7.8 Hz), 7.75 (1H, dd, J=7.8, 2.0 Hz), 7.99-8.07 (1H, m), 8.63(1H, d, J=2.0 Hz).

MS m/z: 481 (M⁺+H).

Example 364[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl4-nitrophenyl=carbonate

To a solution of the2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-(hydroxylmethyl)pyridine(41 mg, 0.10 mmol), which had been obtained in Example 331, indichloromethane (0.5 ml) were added N-methylmorpholine (0.033 ml, 0.30mmol) and 4-nitrophenyl chloroformate (40 mg, 0.20 mmol) at 0° C. Theresulting mixture was stirred at room temperature for 1 hour. Thereaction mixture was washed with water. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel chromatography. A fraction obtained from the elution portionwith hexane:ethyl acetate=4:1 was concentrated under reduced pressure.The solid thus obtained was washed with hexane and collected byfiltration, whereby the title compound (52 mg, 0.090 mmol, 90%) wasobtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 5.33 (2H, s), 5.97 (1H, s), 6.87-6.95 (1H,m), 6.98-7.06 (1H, m), 7.39 (2H, d, J=9.0 Hz), 7.40 (2H, d, J=8.5 Hz),7.57 (2H, d, J=8.5 Hz), 7.71 (1H, d, J=7.6 Hz), 7.85 (1H, dd, J=7.6, 2.0Hz), 7.97-8.05 (1H, m), 8.29 (2H, d, J=9.0 Hz), 8.72 (1H, d, J=2.0 Hz).

MS m/z: 575 (M⁺+H).

Example 365[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methylbenzylcarbamate

To a solution of the[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl4-nitrophenyl carbonate (51 mg, 0.089 mmol) in dichloromethane (1 ml)were successively added N-methylmorpholine (0.020 ml, 0.18 mmol) andbenzylamine (0.012 ml, 0.11 mmol) at 0° C. The resulting mixture wasstirred at room temperature for 20 hours. The reaction mixture waswashed with a saturated aqueous solution of ammonium chloride. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel chromatography. A fractionobtained from the elution portion with hexane:ethyl acetate=4:1 wasconcentrated under reduced pressure. The solid thus obtained was washedwith diisopropyl ether and collected by filtration, whereby the titlecompound (33 mg, 0.060 mmol, 68%) was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 4.38 (2H, brd, J=5.4 Hz), 5.06 (1H, brs),5.16 (2H, s), 5.94 (1H, s), 6.87-7.04 (2H, m), 7.22-7.38 (5H, m), 7.39(2H, d, J=8.3 Hz), 7.54 (2H, d, J=8.3 Hz), 7.62 (1H, d, J=8.3 Hz), 7.74(1H, d, J=8.3 Hz), 7.96-8.03 (1H, m), 8.61 (1H, s).

MS m/z: 543 (M⁺+H).

Example 366N-[[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl]-3-cyanobenzenesulfonamide

To a solution of the6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(28 mg, 0.068 mmol), which had been obtained in Example 351, indichloromethane (0.5 ml) were successively added N-methylmorpholine(0.015 ml, 0.14 mmol) and 3-cyanobenzenesulfonyl chloride (22 mg, 0.10mmol) at 0° C. The resulting mixture was stirred at room temperature for6 hours. After washing with 1N hydrochloric acid, the organic layer wasdried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography and a fraction obtainedfrom the elution portion with hexane:ethyl acetate=7:3 was concentratedunder reduced pressure. The solid thus obtained was washed with hexaneand collected by filtration, whereby the title compound (23 mg, 0.040mmol, 59%) was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 4.26 (2H, d, J=6.4 Hz), 5.08 (1H, t, J=6.4Hz), 5.91 (1H, s), 6.86-7.06 (2H, m), 7.40 (2H, d, J=8.1 Hz), 7.55 (2H,d, J=8.1 Hz), 7.57-7.70 (3H, m), 7.81 (1H, d, J=7.4 Hz), 7.94-8.05 (2H,m), 8.11 (1H, s), 8.46 (1H, s).

MS m/z: 574 (M⁺+H).

Example 367N-[[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl]-3-cyano-N-methylbenzenesulfonamide

To a solution ofN-[[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl]-3-cyanobenzenesulfonamide(21 mg, 0.037 mmol) in tetrahydrofuran (0.5 ml) were successively addedmethanol (0.003 ml, 0.073 mmol), triphenylphosphine (19 mg, 0.073 mmol)and diisopropyl azodicarboxylate (0.014 ml, 0.073 mmol) at 0° C. Theresulting mixture was stirred at room temperature for 2 hours. Thereaction mixture was concentrated under reduced pressure. The residuethus obtained was subjected to flash silica gel chromatography. Afraction obtained from the elution portion with hexane:ethyl acetate=2:1was concentrated under reduced pressure, whereby the title compound (13mg, 0.021 mmol, 58%) was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 2.70 (3H, s), 4.25 (2H, d, J=6.4 Hz), 5.95(1H, s), 6.87-7.05 (2H, m), 7.40 (2H, d, J=8.5 Hz), 7.56 (2H, d, J=8.5Hz), 7.66 (1H, d, J=8.1 Hz), 7.73 (1H, t, J=7.8 Hz), 7.81 (1H, dd,J=8.1, 2.2 Hz), 7.91 (1H, d, J=7.8 Hz), 7.99-8.09 (2H, m), 8.12 (1H, s),8.53 (1H, t, J=2.2 Hz).

MS m/z: 588 (M⁺+H).

Example 3683-[[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl]-1,1-dimethylurea

To a solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(31 mg, 0.076 mmol), which had been obtained in Example 351, indichloromethane (1 ml) were successively added triethylamine (0.032 ml,0.23 mmol), and N,N-dimethylcarbamoyl chloride (0.014 ml, 0.15 mmol) at0° C. The resulting mixture was stirred at room temperature for 17hours. Triethylamine (0.032 ml, 0.23 mmol) and N,N-dimethylcarbamoylchloride (0.014 ml, 0.15 mmol) were added further to the reactionmixture at 0° C. The resulting mixture was stirred at room temperaturefor 29 hours. After the reaction mixture was washed with a saturatedaqueous solution of sodium bicarbonate, the organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel chromatography. A fraction obtained from the elution portionwith ethyl acetate was concentrated under reduced pressure. Theresulting solid was washed with hexane and collected by filtration,whereby the title compound (18 mg, 0.036 mmol, 48%) was obtained as awhite solid.

¹H-NMR (400 MHz, CDCl₃) δ: 2.93 (6H, s), 4.44 (2H, d, J=4.2 Hz), 4.76(1H, t, J=4.2 Hz), 5.93 (1H, s), 6.85-7.04 (2H, m), 7.39 (2H, d, J=8.3Hz), 7.56 (2H, d, J=8.3 Hz), 7.58 (1H, d, J=8.5 Hz), 7.74 (1H, dd,J=8.5, 2.0 Hz), 7.98-8.06 (1H, m), 8.57 (1H, d, J=2.0 Hz).

MS m/z: 480 (M⁺+H).

Example 369 Methyl[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methylcarbamate

In a similar manner to Example 368 except for the use of[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(34 mg, 0.082 mmol) obtained in Example 351 and methyl chlorocarbonate(0.019 ml, 0.25 mmol), the title compound (16 mg, 0.034 mmol, 42%) wasobtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 3.71 (3H, s), 4.40 (2H, d, J=6.1 Hz), 5.07(1H, brs), 5.93 (1H, s), 6.87-7.04 (2H, m), 7.39 (2H, d, J=8.5 Hz), 7.55(2H, d, J=8.5 Hz), 7.60 (1H, d, J=7.8 Hz), 7.70 (1H, d, J=7.8 Hz),7.97-8.04 (1H, m), 8.55 (1H, s).

MS m/z: 467 (M⁺+H).

Example 370N-[[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl]methanesulfonamide

In a similar manner to Example 368 except for the use of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(34 mg, 0.082 mmol) obtained in Example 351 and methanesulfonyl chloride(0.019 ml, 0.25 mmol), the title compound was obtained (20 mg, 0.040mmol, 49%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 2.97 (3H, s), 4.37 (2H, d, J=6.1 Hz), 4.70(1H, brs), 5.95 (1H, s), 6.88-7.07 (2H, m), 7.40 (2H, d, J=8.3 Hz), 7.56(2H, d, J=8.3 Hz), 7.65 (1H, d, J=8.1 Hz), 7.80 (1H, d, J=8.1 Hz),7.97-8.07 (1H, m), 8.61 (1H, s).

MS m/z: 487 (M⁺+H).

Example 371N-[[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl]-1-acetyl-4-piperidinecarboxamide

In a similar manner to Example 368 except for the use of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(34 mg, 0.082 mmol) and 1-acetyl-4-piperidinecarbonyl chloride (56 mg,0.25 mmol), The title compound (24 mg, 0.043 mmol, 52%) was obtained asa colorless foam.

¹H-NMR (400 MHz, CDCl₃) δ: 1.58-1.79 (2H, m), 1.82-1.95 (2H, m), 2.09(3H, s), 2.30-2.41 (1H, m), 2.59-2.70 (1H, m), 3.03-3.13 (1H, m),3.82-3.92 (1H, m), 4.41-4.53 (2H, m), 4.55-4.63 (1H, m), 5.90-5.98 (2H,m), 6.85-6.94 (1H, m), 6.97-7.04 (1H, m), 7.40 (2H, d, J=8.5 Hz), 7.55(2H, d, J=8.5 Hz), 7.60 (1H, d, J=8.1 Hz), 7.66 (1H, d, J=8.1 Hz),7.98-8.05 (1H, m), 8.53 (1H, s).

MS m/z: 562 (M⁺+H).

Example 372[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methylcarbonate

Pyridine (0.040 ml, 0.49 mmol) and methyl chloroformate (0.019, 0.24mmol) were successively added to a solution of the2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-(hydroxymethyl)pyridine(50 mg, 0.12 mmol), which had been obtained in Example 331, indichloromethane (2 ml) at 0° C. and the resulting mixture was stirred atroom temperature for 1 hour. Methyl chloroformate (0.019, 0.24 mmol) wasthen added to the reaction mixture at 0° C., followed by stirring atroom temperature for 5 hours. The reaction mixture was washed with 1Nhydrochloric acid. The organic layer was dried over anhydrous sodiumsulfate and then filtered. The filtrate was concentrated under reducedpressure. The residue was subjected to flash silica gel chromatography.A fraction obtained from the elution portion with hexane:ethylacetate=4:1 was concentrated under reduced pressure. The solid thusobtained was washed with hexane and collected by filtration, whereby thetitle compound (50 mg, 0.11 mmol, 88%) was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 3.81 (3H, s), 5.18 (2H, s), 5.95 (1H, s),6.89-7.04 (2H, m), 7.40 (2H, d, J=8.5 Hz), 7.55 (2H, d, J=8.5 Hz), 7.65(1H, d, J=8.1 Hz), 7.78 (1H, dd, J=8.1, 2.2 Hz), 7.97-8.03 (1H, m), 8.64(1H, d, J=2.2 Hz).

MS m/z: 468 (M⁺+H).

Example 373[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehydeoxime (Isomer 373-A and Isomer 373-B)

To a solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde(100 mg, 0.25 mmol), which had been obtained in Example 335, indichloromethane (3 ml) were added N-methylmorpholine (32 l, 0.29 mmol)and hydroxylamine hydrochloride (26 mg, 0.36 mmol). The resultingmixture was stirred at room temperature for 3 days. The reaction mixturewas diluted with dichloromethane, followed by successive washing withwater, a saturated aqueous solution of sodium bicarbonate and brine. Theorganic layer thus obtained was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column. A fraction obtained from theelution portion with hexane:ethyl acetate=3:2 was concentrated underreduced pressure, whereby the title isomer 373-A (low polarity compound)(79 mg, 0.19 mmol, 72%) was obtained as a white powder and the titleisomer 373-B (high polarity compound) (17 mg, 0.040 mmol, 17%) wasobtained as a white powder.

Isomer 373-A

¹H-NMR (400 MHz, CDCl₃) δ: 5.97 (1H, s), 6.91-6.96 (1H, m), 6.99-7.05(1H, m), 7.40 (2H, d, J=8.6 Hz), 7.56 (2H, d, J=8.6 Hz), 7.66 (1H, d,J=8.1 Hz), 7.78 (1H, s), 7.96-8.02 (2H, m), 8.14 (1H, s), 8.75 (1H, d,J=1.7 Hz).

IR (ATR) cm⁻¹: 3237, 1589, 1594, 1475, 1428, 1394, 1322, 1280, 1236,1151, 1083, 1014.

mp: 187-188° C.

MS m/z: 423 (M⁺+H).

Isomer 373-B

¹H-NMR (400 MHz, CDCl₃) δ: 5.98 (1H, s), 6.91-6.97 (1H, m), 7.00-7.06(1H, m), 7.40 (1H, s), 7.41 (2H, d, J=8.6 Hz), 7.57 (2H, d, J=8.6 Hz),7.71 (1H, d, J=8.3 Hz), 7.90-8.02 (2H, m), 8.41 (1H, dd, J=8.3, 2.1 Hz),9.00 (1H, s).

IR (ATR) cm⁻¹: 3037, 1569, 1492, 1430, 1394, 1324, 1276, 1236, 1153,1081, 1012.

mp: 194-196° C.

MS m/z: 423 (M⁺+H).

Example 3746-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-N-cyclohexylmethylnicotinamide

Triethylamine (32 l, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44mg, 0.23 mmol) and aminomethylcyclohexane (30 l, 0.23 mmol) were addedto a solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (80 mg, 0.19 mmol), which had been obtained in Example 338, indichloromethane (5 ml). The resulting mixture was stirred at roomtemperature for 4.5 hours. The reaction mixture was diluted withdichloromethane, followed by successive washing with water, a saturatedaqueous solution of sodium bicarbonate and brine. The organic layer thusobtained was dried over magnesium sulfate and then concentrated underreduced pressure. The residue was subjected to flash chromatography on asilica gel column and a fraction obtained from the elution portion withhexane:ethyl acetate=3:1 was concentrated under reduced pressure,whereby the title compound (58 mg, 0.11 mmol, 59%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 0.95-1.80 (11H, m), 3.32 (2H, d, J=6.4 Hz),5.98 (1H, s), 6.13-6.16 (1H, m), 6.90-6.96 (1H, m), 7.00-706 (1H, m),7.40 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz), 7.69 (1H, d, J=8.3 Hz),7.97-8.02 (1H, m), 8.13 (1H, dd, J=8.3, 2.2 Hz), 8.94 (1H, d, J=2.2 Hz).

MS m/z: 519 (M⁺+H).

Example 3756-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-N-(5-chloropyridin-2-yl)nicotinamide

Triethylamine (32 l, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44mg, 0.23 mmol) and 2-amino-5-chloropyridine (29 mg, 0.23 mmol) wereadded to the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (80 mg, 0.19 mmol), which had been obtained in Example 338, indichloromethane (5 ml). The resulting mixture was stirred at roomtemperature for 5 hours. The reaction mixture was diluted withdichloromethane, followed by successive washing with water, a saturatedaqueous solution of sodium bicarbonate and brine. The organic layer thusobtained was dried over magnesium sulfate and then concentrated underreduced pressure. The residue was subjected to flash chromatography on asilica gel column and a fraction obtained from the elution portion withhexane:ethyl acetate=3:1 was concentrated under reduced pressure,whereby the title compound (27 mg, 0.051 mmol, 27%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 6.04 (1H, s), 6.92-6.97 (1H, m), 7.01-707(1H, m), 7.42 (2H, d, J=8.6 Hz), 7.57 (2H, d, J=8.6 Hz), 7.75 (1H, dd,J=9.1, 2.4 Hz), 7.80 (1H, d, J=8.1 Hz), 7.97-8.01 (1H, m), 8.26 (1H, dd,J=8.1, 2.2 Hz), 8.28 (1H, d, J=2.4 Hz) 8.33 (1H, d, J=9.1 Hz), 8.51 (1H,s), 9.12 (1H, d, J=2.2 Hz).

MS m/z: 534 (M⁺+H).

Example 376N′,N′-Dimethyl-6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinicacid hydrazide

Triethylamine (32 l, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44mg, 0.23 mmol) and 1,1-dimethylhydrazine (21 l, 0.23 mmol) were added tothe[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (80 mg, 0.19 mmol), which had been obtained in Example 338, indichloromethane (5 ml). The resulting mixture was stirred at roomtemperature for 7 hours. The reaction mixture was diluted withdichloromethane, followed by successive washing with water, a saturatedaqueous solution of sodium bicarbonate and brine. The organic layer thusobtained was dried over magnesium sulfate and then concentrated underreduced pressure. The residue was subjected to flash chromatography on asilica gel column and a fraction obtained from the elution portion withdichloromethane:methanol=50:1 was concentrated under reduced pressure,whereby the title compound (60 mg, 0.13 mmol, 68%) was obtained as acolorless amorphous substance.

¹H-NMR (400 MHz, CDCl₃) δ: 2.57 (0.9H, s), 2.72 (5.1H, s), 5.98 (1H, s),6.48 (0.15H, s), 6.90-7.06 (2.85H, m), 7.41 (2H, d, J=8.6 Hz), 7.56 (2H,d, J=8.6 Hz), 7.68 (1H, d, J=8.1 Hz), 7.97-8.04 (1H, m), 8.13-8.17 (1H,m), 8.94 (0.85H, s), 9.07 (0.15H, s).

MS m/z: 466 (M⁺+H).

Example 377N′-(Furan-2-carbonyl)-6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinicacid hydrazide

Triethylamine (32 l, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44mg, 0.23 mmol) and 2-furoic acid hydrazide (29 mg, 0.23 mmol) were addedto a solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (80 mg, 0.19 mmol), which had been obtained in Example 338, indichloromethane (5 ml). The resulting mixture was stirred at roomtemperature for 7.5 hours. The reaction mixture was diluted withdichloromethane, followed by successive washing with water, a saturatedaqueous solution of sodium bicarbonate and brine. The organic layer thusobtained was dried over magnesium sulfate and then concentrated underreduced pressure. The residue was subjected to flash chromatography on asilica gel column and a fraction obtained from the elution portion withdichloromethane:methanol=50:1 was concentrated under reduced pressure.The solid thus obtained was recrystallized from dichloromethane-hexane,whereby the title compound (58 mg, 0.11 mmol, 58%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 6.01 (0.7H, s), 6.02 (0.3H, s), 6.55 (0.7H,dd, J=3.4, 1.7 Hz), 6.91-6.96 (1H, m), 6.99-7.04 (1H, m), 7.21 (0.7H, d,J=3.4 Hz), 7.41 (2H, d, J=8.6 Hz), 7.53 (0.3H, dd, J=1.7, 0.7 Hz),7.56-7.60 (3H, m), 7.74 (1H, d, J=8.3 Hz), 7.77 (0.3H, d, J=8.8 Hz),7.95-7.99 (1H, m), 8.15-8.19 (1H, m), 8.99 (0.3H, s), 9.03 (1H, d, J=2.2Hz), 9.14 (0.7H, brs), 9.67 (0.7H, brs), 9.98 (0.3H, brs).

MS m/z: 532 (M⁺+H).

Example 378N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-(E)-3-(pyridin-4-yl)acrylamide

To a solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(41 mg, 0.10 mmol) obtained in Example 351, (E)-3-(pyridin-4-yl)acrylicacid (15 mg, 0.10 mmol), benzotriazol-1-ol (14 mg, 0.10 mmol), andN-methylmorpholine (0.011 ml, 0.10 mmol) in dichloromethane (1 ml) wasadded 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19mg, 0.10 mmol) at 0° C. The resulting mixture was stirred at roomtemperature for 19 hours. The reaction mixture was washed with asaturated aqueous solution of sodium bicarbonate. The organic layer thusobtained was dried over anhydrous sodium sulfate and then filtered. Thefiltrate was concentrated under reduced pressure. The residue wassubjected to flash silica gel chromatography and a fraction obtainedfrom the elution portion with ethyl acetate was concentrated underreduced pressure. The solid thus obtained was washed with diethyl etherand then collected by filtration, whereby the title compound (35 mg,0.065 mmol, 65%) was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 4.53-4.66 (2H, m), 5.93 (1H, s), 6.09-6.17(1H, m), 6.57 (1H, d, J=15.6 Hz), 6.86-6.93 (1H, m), 6.96-7.04 (1H, m),7.34 (2H, d, J=5.9 Hz), 7.40 (2H, d, J=8.5 Hz), 7.56 (2H, d, J=8.5 Hz),7.60 (1H, d, J=15.6 Hz), 7.61 (1H, d, J=8.1 Hz), 7.74 (1H, dd, J=8.1,2.2 Hz), 7.99-8.06 (1H, m), 8.59 (1H, d, J=2.2 Hz), 8.64 (2H, d, J=5.9Hz).

MS m/z: 540 (M⁺+H).

Example 379[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl](thiomorpholin-4-yl)methanone

In a similar manner to Example 378 except for the use of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (212 mg, 0.50 mmol) obtained in Example 338 and thiomorpholine(0.047 ml, 0.50 mmol), the title compound (240 mg, 0.47 mmol, 94%) wasobtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 2.61 (2H, br s), 2.74 (2H, br s), 3.69 (2H,br s), 4.04 (2H, br s), 5.97 (1H, s), 6.88-6.95 (1H, m), 6.98-7.06 (1H,m), 7.41 (2H, d, J=8.5 Hz), 7.57 (2H, d, J=8.5 Hz), 7.73 (1H, d, J=8.1Hz), 7.79 (1H, dd, J=8.1, 2.2 Hz), 7.95-8.02 (1H, m), 8.64 (1H, d, J=2.2Hz).

MS m/z: 509 (M⁺+H).

Example 380[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl](1,1-dioxo-1λ⁶-thiomorpholin-4-yl)methanone(Compound A) and[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl](1-oxo-1λ⁴-thiomorpholin-4-yl)methanone(Compound B)

Compound A Compound B

Under ice cooling, 3-chloroperbenzoic acid (96 mg, 0.36 mmol) was addedto a solution of[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl](thiomorpholin-4-yl)methanone(153 mg, 0.30 mmol) in dichloromethane (3 ml) and the mixture wasstirred at room temperature for 2 hours. The reaction mixture wasdiluted with dichloromethane, followed by successive washing with a 1Naqueous solution of sodium hydroxide and brine. The organic layer thusobtained was dried over magnesium sulfate and concentrated under reducedpressure. The residue was subjected to flash chromatography on a silicagel column. A fraction obtained from the elution portion withhexane:ethyl acetate=1:2 was concentrated under reduced pressure,whereby the title compound A (low polarity compound) (81 mg, 0.15 mmol,50%) was obtained as a white powder. A fraction obtained from theelution portion with dichloromethane:methanol=10:1 was concentratedunder reduced pressure, whereby the title compound B (high polaritycompound) (73 mg, 0.14 mmol, 46%) was obtained as a white powder.

Compound A

¹H-NMR (400 MHz, CDCl₃) δ: 3.10 (4H, brs), 4.13 (4H, brs), 5.99 (1H, s),6.88-6.93 (1H, m), 7.00-7.06 (1H, m), 7.42 (2H, d, J=8.5 Hz), 7.58 (2H,d, J=8.5 Hz), 7.79 (1H, d, J=8.1 Hz), 7.86 (1H, dd, J=8.1, 1.7 Hz),7.97-8.02 (1H, m), 8.71 (1H, d, J=1.7 Hz).

MS m/z: 541 (M⁺+H).

Compound B

¹H-NMR (400 MHz, CDCl₃) δ: 2.70-3.00 (4H, m), 3.74 (1H, brs), 4.10 (2H,brs), 4.63 (1H, brs), 5.98 (1H, s), 6.88-6.94 (1H, m), 7.00-7.06 (1H,m), 7.42 (2H, d, J=8.6 Hz), 7.58 (2H, d, J=8.6 Hz), 7.77 (1H, d, J=8.1Hz), 7.84 (1H, dd, J=8.1, 2.2 Hz), 7.98-8.02 (1H, m), 8.70 (1H, d, J=2.2Hz)

MS m/z: 525 (M⁺+H).

Example 381N-(3-Methylthiopropyl)-6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinamide

In a similar manner to Example 378 except for the use of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (212 mg, 0.50 mmol) obtained in Example 338 and3-methylthiopropylamine (0.055 ml, 0.50 mmol), the title compound (238mg, 0.47 mmol, 93%) was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.92-2.01 (2H, m), 2.14 (3H, s), 2.63 (2H, t,J=6.8 Hz), 3.58-3.64 (2H, m), 5.99 (1H, s), 6.57-6.64 (1H, m), 6.90-6.97(1H, m), 6.99-7.06 (1H, m), 7.41 (2H, d, J=8.5 Hz), 7.56 (2H, d, J=8.5Hz), 7.71 (1H, d, J=8.1 Hz), 7.96-8.03 (1H, m), 8.16 (1H, dd, J=8.1, 2.2Hz), 8.96 (1H, d, J=2.2 Hz).

MS m/z: 511 (M⁺+H).

Example 382N-(3-Methylsulfonylpropyl)-6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinamide(Compound A) andN-(3-methylsulfinylpropyl)-6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinamide(Compound B)

Compound A Compound B

To a solution ofN-(3-methylthiopropyl)-6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinamide(153 mg, 0.30 mmol) in dichloromethane (3 ml) was added3-chloroperbenzoic acid (purity: 65% or greater) (96 mg, 0.36 mmol) at0° C. The resulting mixture was stirred at room temperature for 3 hours.The reaction mixture was washed with a 1N aqueous solution of sodiumhydroxide. The organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure. Theresidue was subjected to flash silica gel chromatography. A fractionobtained from the elution portion with ethyl acetate was concentratedunder reduced pressure. The solid thus obtained was washed with diethylether and then collected by filtration, whereby the title compound A (53mg, 0.098 mmol, 32%) was obtained as a white solid. Then, a fractionobtained from the elution portion with dichloromethane:methanol ˜15:1was concentrated under reduced pressure. The solid thus obtained waswashed with diethyl ether and collected by filtration, whereby the titlecompound B (68 mg, 0.13 mmol, 43%) was obtained as a white solid.

Compound A

¹H-NMR (400 MHz, CDCl₃) δ: 2.20-2.30 (2H, m), 2.98 (3H, s), 3.17 (2H, t,J=6.8 Hz), 3.65-3.72 (2H, m), 5.99 (1H, s), 6.82-6.88 (1H, m), 6.90-6.97(1H, m), 6.99-7.06 (1H, m), 7.41 (2H, d, J=8.5 Hz), 7.56 (2H, d, J=8.5Hz), 7.72 (1H, d, J=8.1 Hz), 7.96-8.02 (1H, m), 8.16 (1H, dd, J=8.1, 2.2Hz), 9.00 (1H, d, J=2.2 Hz).

MS m/z: 543 (M⁺+H).

Compound B

¹H-NMR (400 MHz, CDCl₃) δ: 2.11-2.23 (1H, m), 2.26-2.37 (1H, m), 2.63(3H, s), 2.78-2.86 (1H, m), 2.92-3.00 (1H, m), 3.51-3.61 (1H, m),3.66-3.75 (1H, m), 5.99 (1H, s), 6.90-6.98 (1H, m), 6.99-7.06 (1H, m),7.40 (2H, d, J=8.5 Hz), 7.55 (2H, d, J=8.5 Hz), 7.69 (1H, d, J=8.1 Hz),7.88-8.01 (2H, m), 8.22 (1H, dd, J=8.1, 2.2 Hz), 9.08 (1H, d, J=2.2 Hz).

MS m/z: 527 (M⁺+H).

Example 3832-Chloro-5-[(3-chloropyridin-4-yl)(2,5-difluorophenyl)methylthio]pyridine

A 1N aqueous solution of sodium hydroxide (7 ml) was added to a solutionof the S-(6-chloro-3-pyridyl) O-ethyl dithiocarbonate (164 mg, 0.70mmol) obtained in Referential Example 33 and the mixture was stirred at80° C. for 3 hours. After cooling the reaction mixture to roomtemperature, 1N hydrochloric acid was added, followed by extraction withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate and then filtered. The filtrate was concentrated under reducedpressure to yield 6-chloro-3-pyridinethiol as a yellow solid.

To a solution of the3-chloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (153 mg, 0.60mmol), which had been obtained in Referential Example 48, indichloromethane (3 ml) were added triethylamine (0.167 ml, 1.20 mmol)and methanesulfonyl chloride (0.070 ml, 0.90 mmol) at 0° C. and themixture was stirred at room temperature for 2 hours. The reactionmixture was washed with a saturated aqueous solution of sodiumbicarbonate. The organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated under reduced pressure.

A solution of 6-chloro-3-pyridinethiol in N,N-dimethylformamide (2 ml)and potassium carbonate (100 mg, 0.72 mmol) were added successively to asolution of the resulting residue in N,N-dimethylformamide (3 ml). Theresulting mixture was stirred at room temperature for 18 hours. Ethylacetate was added to the reaction mixture. The resulting mixture waswashed with a saturated aqueous solution of sodium bicarbonate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. The residue wassubjected to flash silica gel chromatography. A fraction obtained fromthe elution portion with hexane:ethyl acetate=17:3 was concentratedunder reduced pressure, whereby the title compound (111 mg, 0.29 mmol,48%) was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.04 (1H, s), 6.95-7.05 (2H, m), 7.10-7.20(1H, m), 7.25 (1H, d, J=8.1 Hz), 7.57 (1H, d, J=5.1 Hz), 7.60 (1H, dd,J=8.1, 2.5 Hz), 8.31 (1H, d, J=2.5 Hz), 8.54 (1H, d, J=5.1 Hz), 8.59(1H, s).

MS m/z: 383 (M⁺+H).

Example 3842-Chloro-5-[(3-chloropyridin-4-yl)(2,5-difluorophenyl)methylsulfonyl]pyridine

A 31% aqueous hydrogen peroxide solution (2 ml) and hexaammoniumheptamolybdate tetrahydrate (30 mg) were added to a solution of2-chloro-5-[(3-chloropyridin-4-yl)(2,5-difluorophenyl)methylthio]pyridine(109 mg, 0.28 mmol) in methanol (4 ml) were added and the mixture wasstirred at room temperature for 17 hours. Ethyl acetate was added to thereaction mixture, followed by washing with a saturated aqueous solutionof sodium bicarbonate. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure. The residue was subjected to flash silica gel chromatographyand a fraction obtained from the elution portion with hexane:ethylacetate=17:3 was concentrated under reduced pressure, whereby the titlecompound (108 mg, 0.26 mmol, 92%) was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.26 (1H, s), 6.94-7.03 (1H, m), 7.06-7.15(1H, m), 7.44 (1H, d, J=8.3 Hz), 7.50-7.56 (1H, m), 7.89 (1H, dd, J=8.3,2.7 Hz), 8.12 (1H, d, J=5.1 Hz), 8.59 (1H, d, J=2.7 Hz), 8.61 (1H, s),8.66 (1H, d, J=5.1 Hz).

MS m/z: 415 (M⁺+H).

Example 3855-[(3-Chloropyridin-4-yl)(2,5-difluorophenyl)methylsulfonyl]-2-fluoropyridine

Potassium fluoride (94 mg, 1.60 mmol) and tetraphenylphosphonium bromide(134 mg, 0.32 mmol) were added to a solution of2-chloro-5-[(3-chloropyridin-4-yl)(2,5-difluorophenyl)methylsulfonyl]pyridine(66 mg, 0.16 mmol) in acetonitrile (2 ml). The resulting mixture washeated under reflux for 16 hours. The reaction mixture was cooled toroom temperature. Dichloromethane was added and the mixture was washedwith water. The organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated under reduced pressure. Theresidue was subjected to flash chromatography on a silica gel column anda fraction obtained from the elution portion with hexane:ethylacetate=17:3 was concentrated under reduced pressure, whereby the titlecompound (4.5 mg, 0.011 mmol, 7%) was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.26 (1H, s), 6.93-7.13 (3H, m), 7.50-7.56(1H, m), 8.01-8.08 (1H, m), 8.13 (1H, d, J=5.1 Hz), 8.48 (1H, d, J=2.2Hz), 8.60 (1H, s), 8.66 (1H, d, J=5.1 Hz).

MS m/z: 440 (M⁺+H+MeCN).

Example 386N′-[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-ylmethylidene]-2-thiophenecarbohydrazide

The[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde(100 mg, 0.245 mmol) obtained in Example 335 and2-thiophenecarbohydrazide (41.7 mg, 0.294 mmol) were dissolved inethanol (3 ml). The resulting solution was stirred at room temperaturefor 3 days. The solid thus precipitated was collected by filtration andwashed with ethanol. The resulting solid was recrystallized fromethanol, whereby the title compound (91.0 mg, 0.171 mol, 70%) wasobtained as a white solid.

¹H-NMR (400 MHz, CDCl₃/DMSO-d₆) δ: 5.98 (1H, s), 6.93-7.01 (1H, m),7.02-7.09 (1H, m), 7.14-7.20 (1H, br m), 7.42 (2H, d, J=8.5 Hz), 7.57(2H, d, J=8.5 Hz), 7.62-7.73 (2H, br m), 8.02-8.20 (3H, m), 8.95 (1H,s), 11.5 (1H, s).

IR (ATR) cm⁻¹: 3302, 1655, 1597, 1541, 1489, 1419, 1394, 1321, 1279,1149, 1078, 1016, 966, 889, 831, 822, 762, 725, 710, 611, 552, 509, 465.

MS m/z: 532 (M⁺+H).

Example 3876-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinamide

Thionyl chloride (1.00 ml) and N,N-dimethylformamide (one drop) wereadded to a suspension of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (100 mg, 0.236 mmol), which had been obtained in Example 338, indichloromethane (4 ml). The resulting mixture was stirred at roomtemperature for 18 hours. The reaction mixture was concentrated todryness. The residue was then dissolved in dichloromethane (6 ml),followed by the addition of 28% aqueous ammonia (2 ml). After thereaction mixture was stirred at room temperature for 3 hours, it wasacidified with 1N hydrochloric acid. The resulting mixture wasconcentrated and the solid thus formed was collected by filtration. Thesolid was washed with water and ethanol and then recrystallized fromethanol, whereby the title compound (47.9 mg, 0.113 mmol, 46%) wasobtained as a white solid.

¹H-NMR (400 MHz, CDCl₃/DMSO-d₆) δ: 6.00 (1H, s), 6.38 (1H, br s),6.94-6.99 (1H, m), 7.02-7.08 (1H, m), 7.43 (2H, d, J=8.5 Hz), 7.56 (2H,d, J=8.5 Hz), 7.67 (1H, d, J=7.6 Hz), 7.65-7.75 (1H, br m), 7.99-8.04(1H, m), 8.26 (1H, dd, J=8.1, 2.4 Hz), 9.12 (1H, d, J=1.7 Hz).

IR (ATR) cm⁻¹: 3442, 3165, 2954, 1670, 1624, 1595, 1496, 1410, 1373,1313, 1279, 1232, 1176, 1147, 1086, 1012, 831, 816, 754, 710, 667, 606,552, 499, 465.

MS m/z: 423 (M⁺+H).

Example 3886-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-N-(4-methylcyclohexyl)nicotinamide

Thionyl chloride (1.00 ml) and N,N-dimethylformamide (one drop) wereadded to a suspension of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (100 mg, 0.236 mmol), which had been obtained in Example 338, indichloromethane (4 ml). The resulting mixture was stirred at roomtemperature for 6 hours. The reaction mixture was concentrated todryness. The residue was then dissolved in dichloromethane (6 ml),followed by the addition of N-methylmorpholine (51.8 l, 0.472 mmol) and4-methylcyclohexylamine (37.4 l, 0.283 mmol). After the reaction mixturewas stirred at room temperature for 18 hours, the mixture was dilutedwith dichloromethane. The solution was washed successively with 1Nhydrochloric acid, water and brine, dried over magnesium sulfate andconcentrated. The residue was subjected to flash chromatography on asilica gel column. A fraction obtained from the elution portion withhexane:ethyl acetate=3:1 was concentrated, whereby a white solid wasobtained. The resulting solid was recrystallized from ethylacetate-hexane, whereby the title compound (70.3 mg, 0.135 mmol, 57%)was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (1.8H, d, J=6.6 Hz), 0.96 (1.2H, d,J=6.4 Hz), 1.05-1.30 (3H, m), 1.32-1.43 (0.6H, m), 1.55-1.83 (4.4H, m),2.03-2.12 (1H, m), 3.86-3.97 (0.6H, m), 4.20-4.28 (0.4H, m), 5.88 (0.6H,d, J=7.1 Hz), 5.98 (1H, s), 6.18 (0.4H, d, J=7.3 Hz), 6.90-6.96 (1H, m),6.98-7.06 (1H, m), 7.41 (1.2H, d, J=8.1 Hz), 7.41 (0.8H, d, J=8.1 Hz),7.56 (1.2H, d, J=8.1 Hz), 7.57 (0.8H, d, J=8.1 Hz), 7.67-7.72 (1H, m),7.97-8.05 (1H, m), 8.10-8.18 (1H, m), 8.93 (0.6H, d, J=2.2 Hz), 8.96(0.4H, d, J=2.2 Hz). IR (ATR) cm⁻¹: 3381, 2935, 1643, 1595, 1525, 1489,1394, 1317, 1281, 1234, 1171, 1147, 1078, 1016, 966, 897, 831, 823, 764,729, 609, 548, 469, 413.

MS m/z: 519 (M⁺+H).

Example 3896-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-N-methoxynicotinamide

To a suspension of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (100 mg, 0.236 mmol), which had been obtained in Example 338, indichloromethane (6 ml) were added N-methylmorpholine (77.7 l, 0.708mmol), O-methylhydroxylamine hydrochloride (23.6 mg, 0.283 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54.3 mg,0.283 mmol). After stirring at room temperature for 1 hour,tetrahydrofuran (1 ml) was added to the mixture. The reaction mixturewas stirred at room temperature for 18 hours. The mixture was thendiluted with dichloromethane, and washed with water and brine. Theorganic layer thus obtained was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was subjected to flashchromatography on a silica gel column and a fraction obtained from theelution portion with hexane:ethyl acetate=1:1 was concentrated, wherebya white solid was obtained. The solid was washed with ethyl acetate,whereby the title compound (55.1 mg, 0.122 mmol, 52%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 3.90 (2.4H, s), 3.97 (0.6H, s), 5.97 (0.2H,s), 5.98 (0.8H, s), 6.90-7.07 (2H, m), 7.39-7.46 (2H, m), 7.54-7.59 (2H,m), 7.63 (0.2H, d, J=8.3 Hz), 7.73 (0.8H, d, J=8.1 Hz), 7.94-8.00 (1H,m), 8.10-8.15 (1H, m), 8.76 (1H, br s), 8.92 (0.8H, d, J=1.7 Hz), 9.01(0.2H, d, J=1.5 Hz).

MS m/z: 453 (M⁺+H).

Example 390N,N-Dimethyl-6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine

After the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde(100 mg, 0.245 mmol) obtained in Example 335, a tetrahydrofuran solution(2.0M, 0.25 ml, 0.50 mmol) of dimethylamine and acetic acid (0.029 ml,0.51 mmol) were dissolved in 1,2-dichloroethane (5 ml), sodiumtriacetoxyborohydride (115 mg, 0.515 mmol) was added to the resultingsolution at room temperature. The resulting mixture was stirred at roomtemperature for 3 days. A saturated aqueous solution of sodiumbicarbonate and ethyl acetate were added to the reaction mixture. Themixture was separated and the organic layer thus obtained was washedsuccessively with a saturated aqueous solution of sodium bicarbonate andbrine and dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The residue wassubjected to flash silica gel chromatography and a fraction obtainedfrom the elution portion with dichloromethane:methanol=40:1 wasconcentrated under reduced pressure to yield a white solid. The solidwas washed with hexane, whereby the title compound (88 mg, 0.20 mmol,82%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.23 (6H, s), 3.43 (2H, s), 5.94 (1H, s),6.88-6.98 (1H, m), 6.98-7.06 (1H, m), 7.38 (2H, d, J=8.6 Hz), 7.52-7.62(3H, m), 7.71 (1H, dd, J=8.1, 2.1 Hz), 7.98-8.08 (1H, m), 8.51 (1H, d,J=2.1 Hz).

MS m/z: 437 (M⁺+H).

Example 391N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]bis(2-methoxyethyl)amine

After the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde(100 mg, 0.245 mmol) obtained in Example 335, bis(2-methoxyethyl)amine(70 mg, 0.53 mmol) and acetic acid (0.029 ml, 0.51 mmol) were dissolvedin 1,2-dichloroethane (5 ml), sodium triacetoxyborohydride (115 mg,0.515 mmol) was added to the resulting solution at room temperature. Theresulting mixture was stirred at room temperature for 3 days. Asaturated aqueous solution of sodium bicarbonate and ethyl acetate wereadded to the reaction mixture. The mixture was separated and the organiclayer thus obtained was washed successively with a saturated aqueoussolution of sodium bicarbonate and brine and dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated underreduced pressure. The residue was subjected to flash silica gelchromatography and a fraction obtained from the elution portion withhexane:ethyl acetate=3:2 was concentrated under reduced pressure toyield a white solid. The solid was washed with hexane, whereby the titlecompound (101 mg, 0.192 mmol, 78%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.73 (4H, t, J=5.8 Hz), 3.31 (6H, s), 3.47(4H, d, J=5.8 Hz), 3.75 (2H, s), 5.93 (1H, s), 6.88-6.97 (1H, m),6.97-7.07 (1H, m), 7.38 (2H, d, J=8.8 Hz), 7.50-7.60 (3H, m), 7.76 (1H,dd, J=8.1, 2.0 Hz), 7.98-8.08 (1H, m), 8.54 (1H, d, J=2.0 Hz).

MS m/z: 525 (M⁺+H).

Example 3926-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-N,N-dimethylnicotinamide

After the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (90 mg, 0.21 mmol) obtained in Example 338, a tetrahydrofuransolution (2.0M, 0.21 ml, 0.42 mmol) of dimethylamine,4-(dimethylamino)pyridine (15 mg, 0.12 mmol) and triethylamine (0.045ml, 0.32 mmol) were dissolved in dichloromethane (5 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32mmol) was added to the resulting solution at room temperature. Theresulting mixture was stirred at room temperature for 14 hours. Thereaction mixture was concentrated under reduced pressure. The residuethus obtained was subjected to flash silica gel chromatography and afraction obtained from the elution portion with hexane:ethyl acetate=2:1was concentrated under reduced pressure, whereby the title compound (35mg, 0.066 mmol, 90%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 3.01 (3H, s), 3.14 (3H, s), 5.97 (1H, s),6.88-6.99 (1H, m), 6.99-7.08 (1H, m), 7.40 (2H, d, J=8.7 Hz), 7.57 (2H,d, J=8.7 Hz), 7.70 (1H, dd, J=8.0, 0.7 Hz), 7.82 (1H, dd, J=8.0, 2.2Hz), 7.93-8.04 (1H, m), 8.68 (1H, dd, J=2.2, 0.7 Hz).

MS m/z: 451 (M⁺+H).

Example 393[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl](4-methylpiperazin-1-yl)methanone

After the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (90 mg, 0.21 mmol) obtained in Example 338, N-methylpiperazine(0.036 ml, 0.33 mmol), 4-(dimethylamino)pyridine (15 mg, 0.12 mmol) andtriethylamine (0.045 ml, 0.32 mmol) were dissolved in dichloromethane (5ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg,0.32 mmol) was added to the resulting solution at room temperature. Theresulting mixture was stirred at room temperature for 14 hours. To thereaction mixture, N-methylpiperazine (0.036 ml, 0.33 mmol),triethylamine (0.045 ml, 0.32 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32mmol) were added further. The resulting mixture was stirred at roomtemperature for 14 hours, followed by concentration under reducedpressure. The residue thus obtained was subjected to flash silica gelchromatography and a fraction obtained from the elution portion withdichloromethane:methanol=25:1 was concentrated under reduced pressure,whereby the title compound (86 mg, 0.17 mmol, 80%) was obtained as awhite powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.33 (3H, s), 2.38 (2H, br s), 2.50 (2H, brs), 3.44 (2H, br s), 3.81 (2H, br s), 5.97 (1H, s), 6.87-6.98 (1H, m),6.98-7.08 (1H, m), 7.40 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 7.71(1H, dd, J=8.1, 0.7 Hz), 7.81 (1H, dd, J=8.1, 2.2 Hz), 7.94-8.04 (1H,m), 8.66 (1H, dd, J=2.2, 0.7 Hz).

MS m/z: 506 (M⁺+H).

Example 3944-[2-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]aminoethyl]morpholine

The4-[2-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]aminoethyl]morpholine-N-oxide(78 mg, 0.14 mmol) obtained in Example 349 was dissolved in a mixedsolvent of acetic acid (2.0 ml) and water (2.0 ml). The resultingmixture was heated to 60° C. Iron powder (40 mg, 0.72 mmol) was addedand the mixture was stirred for 30 minutes. After cooling, the reactionmixture was poured into a saturated aqueous solution of potassiumcarbonate, followed by extraction with ethyl acetate (60 ml). Thesolution was washed with brine, dried and then concentrated underreduced pressure. The residue was purified by silica gel chromatography(3% methanol/chloroform solution), whereby the title compound (30 mg,40%) was obtained.

¹H-NMR (400 MHz, CDCl₃) δ: 2.5-2.8 (6H, m), 3.59 (2H, br), 3.81 (4H,br), 5.45 (1H, br), 6.10 (1H, s), 6.88 (1H, m), 7.01 (1H, m), 7.25 (1H,s), 7.42 (2H, d, J=8.8 Hz), 7.49 (1H, m), 7.60 (2H, d, J=8.4 Hz), 7.97(1H, s).

MS m/z: 542 (M⁺+H).

Example 395 tert-Butyl2-[N-[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-methylamino]ethyl-methylcarbamate

A solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(78 mg, 0.19 mmol) obtained in Example 342 andN,N′-dimethylethylenediamine (400 μl) in 1,4-dioxane (2.0 ml) wasstirred at 100° C. for 2 days under nitrogen atmosphere. After coolingto room temperature, the reaction mixture was diluted with ethyl acetate(40 ml). The solution was washed with water and brine, dried and then,concentrated under reduced pressure.

The residue thus obtained was dissolved in tetrahydrofuran (10 ml),followed by the addition of triethylamine (31 μl, 0.22 mmol) anddi-tert-butyl dicarbonate (49 mg, 0.22 mmol) at room temperature. Theresulting mixture was stirred for 15 hours. After the solution wasconcentrated under reduced pressure, the residue was purified by silicagel chromatography (hexane:ethyl acetate=4:1), whereby the titlecompound (68 mg, 64%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.26 and 1.32 (9H, br-s, rotamer), 2.75 and2.78 (3H, br-s, rotamer), 2.95 (3H, br-s), 3.30 (2H, m), 3.65 (2H, m),5.92 (1H, s), 6.6-6.8 (1H, m), 6.84-6.97 (2H, m), 7.05 (1H, m), 7.14(2H, d, J=8.8 Hz), 7.17 (2H, d, J=8.4 Hz), 7.98 (1H, s).

MS m/z: 568 (M⁺+H).

Example 396 tert-Butyl2-[N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-methylamino]ethyl-methylcarbamate

To a solution of tert-butyl2-[N-[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-methylamino]ethyl-methylcarbamate(67 mg, 0.12 mmol) in methanol (6 ml) was added hexaammoniumheptamolybdate tetrahydrate (30 mg). A 30% aqueous hydrogen peroxidesolution (3 ml) was then added and the mixture was stirred for 17 hours.After dilution with ethyl acetate, the solution was washed with waterand brine, and concentrated under reduced pressure. The residue thusobtained was purified by silica gel chromatography (hexane:ethylacetate=3:1), whereby the title compound (64 mg, 91%) was obtained as anoil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.33 and 1.38 (9H, br-s, rotamer), 2.87 and2.89 (3H, br-s, rotamer), 3.11 (3H, br-s), 3.3-3.4 (2H, m), 3.6-3.9 (2H,m), 6.12 (1H, s), 6.89 (1H, m), 7.00 (1H, m), 7.26 (1H, m), 7.41 (2H, d,J=8.4 Hz), 7.53 (1H, m), 7.59 (2H, d, J=8.4 Hz), 8.00 (1H, s).

MS m/z: 600 (M⁺+H).

EI-MS: 599.1204 (Calcd for C₂₇H₂₉Cl₂F₂N₃O₄S: 599.1224).

Example 3975-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-2-[N-methyl-N-[2-(methylamino)ethyl]amino]pyridine

In methylene chloride (2.0 ml) was dissolved tert-butyl2-[N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine-2-yl]-N-methylamino]ethyl-methylcarbamate(61 mg, 0.10 mmol), followed by the addition of anisole (40 μl) andtrifluoroacetic acid (200 μl) at room temperature. The resulting mixturewas stirred for 1 hour. The residue obtained by concentrating thereaction mixture under reduced pressure was purified by silica gelchromatography (3% methanol/chloroform ˜3% methanol, 3%tertbutylamine/chloroform), whereby the title compound (21 mg, 41%) wasobtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 2.51 (3H, s), 2.90 (2H, d, J=6.0 Hz), 3.14(3H, s), 3.72 (2H, m), 6.13 (1H, s), 6.89 (1H, m), 7.00 (1H, m), 7.36(1H, m), 7.41 (2H, d, J=8.4 Hz), 7.52 (1H, m), 7.60 (2H, d, J=8.4 Hz),8.00 (1H, s).

MS m/z: 500 (M⁺+H).

FAB-MS: 500.0770 (Calcd for C₂₂H₂₂Cl₂F₂N₃O₂S: 500.0778).

Example 398(2′S)-5-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-2-[2′-(hydroxymethyl)pyrrolidin-1′-yl]pyridine

A solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(60 mg, 0.14 mmol), which had been obtained in Example 342, and(S)-2-pyrrolidinemethanol (200 μl) in 1,4-dioxane (1.0 ml) was stirredat 100° C. for 3 days under nitrogen atmosphere. After cooling to roomtemperature, the reaction mixture was diluted with ethyl acetate (50ml). The solution was washed with water and brine, dried andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (hexane:ethyl acetate=5:1), whereby the titlecompound (40 mg, 58%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.78 (1H, m), 2.06 (3H, m), 3.29 (1H, m),3.50 (1H, m), 3.66 (1H, m), 3.72 (1H, m), 4.33 (1H, m), 5.97 and 5.98(1H, s, rotamer), 6.73 and 6.77 (1H, s, rotamer), 6.92-7.15 (3H, m),7.25 (4H, m), 7.98 (1H, s).

MS m/z: 481 (M⁺+H).

Example 399(2′S)-5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl-2-[2′-(hydroxymethyl)pyrrolidin1′-yl]pyridine

Hexaammonium heptamolybdate tetrahydrate (30 mg) was added to a solutionof(2′S)-5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-2-[2′-(hydroxymethyl)pyrrolidin-1′-yl]pyridine(39 mg, 0.08 mmol) in methanol (6 ml). A 30% aqueous hydrogen peroxidesolution (3 ml) was added to the resulting mixture, followed by stirringfor 17 hours. The reaction mixture was diluted with ethyl acetate (60ml). The solution was washed with water and brine, and concentratedunder reduced pressure. The residue was purified by silica gelchromatography (hexane:ethyl acetate=1:1), whereby the title compound(33 mg, 79%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.75 (1H, m), 2.02 (3H, m), 3.3-3.5 (1H, m),3.52-3.75 (3H, m), 4.2-4.35 (1H, m), 6.05 (1H, br-s), 6.84 (1H, m), 6.96(1H, m), 7.36 (1H, s), 7.36 and 7.37 (2H, d, J=8.8 Hz, rotamer), 7.43(1H, m), 7.53 and 7.54 (2H, d, J=8.8 Hz, rotamer), 7.89 and 7.90 (1H, s,rotamer).

MS m/z: 513 (M⁺+H)

FAB-MS: 513.0627 (Calcd for C₂₃H₂₁Cl₂F₇N₂O₃S: 513.0618).

Example 400 t-Butyl[4-[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine-2-yl]morpholine-2-yl]methylcarbamate

A solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(60 mg, 0.14 mmol) obtained in Example 342 and tert-butyl(morpholin-2-yl)methylcarbamate (200 mg) in 1,4-dioxane (1.0 ml) wasstirred at 100° C. for 2 days under nitrogen atmosphere. After coolingto room temperature, the reaction mixture was diluted with ethyl acetate(50 ml). The solution was washed with water and brine, dried andconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel chromatography (hexane:ether=5:1), whereby thetitle compound (45 mg, 52%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.46 (9H, s), 2.72 (1H, m), 3.00 (1H, m),3.22 (1H, m), 3.44 (1H, m), 3.6-3.75 (2H, m), 3.9-4.1 (3H, m), 4.95 (1H,br), 5.99 and 6.00 (1H, s, rotamer), 6.96 and 6.97 (1H, s, rotamer),6.9-7.1 (3H, m), 7.24 (4H, s), 8.11 (1H, s).

MS m/z: 596 (M⁺+H).

Example 401 tert-Butyl[4-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholine-2-yl]methylcarbamate

Hexaammonium heptamolybdate tetrahydrate (30 mg) was added to a solutionof tert-butyl[4-[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine-2-yl]morpholine-2-yl]methylcarbamate(44 mg, 0.074 mmol) in methanol (6 ml). A 30% aqueous hydrogen peroxidesolution (3 ml) was added to the resulting mixture, followed by stirringfor 17 hours. The reaction mixture was diluted with ethyl acetate (60ml). The solution was washed with water and brine, and concentratedunder reduced pressure. The residue thus obtained was purified by silicagel chromatography (hexane:ethyl acetate=3:1), whereby the titlecompound (31 mg, 67%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.40 (9H, s), 2.69 (1H, m), 3.02 (1H, m),3.18 (1H, m), 3.41 (1H, br), 3.6-3.75 (2H, m), 3.92 (1H, m), 4.02 (1H,m), 4.13 (1H, m), 4.91 (1H, br), 6.07 (1H, s), 6.85 (1H, m), 6.99 (1H,m), 7.37 (2H, d, J=8.4 Hz), 7.35-7.45 (2H, m), 7.53 (2H, d, J=8.4 Hz),8.17 (1H, s).

MS m/z: 628 (M⁺+H).

FAB-MS: 628.1255 (Calcd for C₂₈H₃₀Cl₂F₂N₃O₅S: 628.1251).

Example 4022-Aminomethyl-4-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholine

In methylene chloride (1.5 ml) was dissolved tert-butyl[4-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine-2-yl]morpholine-2-yl]methylcarbamate(30 mg, 0.05 mmol). After addition of anisole (30 μl) andtrifluoroacetic acid (150 μl) at room temperature, the mixture wasstirred for 1 hour. The residue obtained by concentrating the reactionmixture under reduced pressure was purified by silica gel chromatography(3% methanol/chloroform→3% methanol, 3% tert-butylamine/chloroform),whereby the title compound (17 mg, 67%) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ: 2.77 (1H, m), 2.9-3.3 (2H, m), 3.5-3.85 (3H,m), 3.97 (1H, m), 4.04-4.25 (2H, m), 6.12 (1H, s), 6.90 (1H, m), 7.02(1H, m), 7.42 (2H, d, J=8.4 Hz), 7.4-7.55 (2H, m), 7.58 (2H, d, J=8.4Hz), 8.05 (1H, s).

MS m/z: 528 (M⁺+H).

FAB-MS: 528.0695 (Calcd for C₂₃H₂₂Cl₂F₂N₃O₃S: 528.0727).

Example 4035-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-2-(4′-hydroxypiperidine-1′-yl)pyridine

A solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(60 mg, 0.14 mmol) obtained in Example 342 and 4-hydroxypiperidine (200mg) was stirred at 100° C. for 1 day under nitrogen atmosphere. Aftercooling to room temperature, the reaction mixture was diluted withdiethyl ether (50 ml). The solution was washed with water and brine,dried and then concentrated under reduced pressure. The residue thusobtained was purified by silica gel chromatography (hexane:ethylacetate=3:1), whereby the title compound (30 mg, 43%) was obtained as anoil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.62 (2H, m), 2.05 (2H, m), 3.30 (2H, m),3.98 (3H, m), 5.97 (1H, s), 6.96-7.12 (3H, m), 7.23 (4H, m), 7.26 (1H,s), 8.10 (1H, s).

MS m/z: 481 (M⁺+H).

Example 4045-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-2-(4′-hydroxypiperidin-1′-yl)pyridine

Hexaammonium heptamolybdate tetrahydrate (30 mg) was added to a solutionof5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-2-(4′-hydroxypiperidin-1′-yl)pyridine(29 mg, 0.06 mmol) in methanol (6 ml). A 30% aqueous hydrogen peroxidesolution (3 ml) was added to the resulting mixture, followed by stirringfor 17 hours. After dilution with ethyl acetate (60 ml), the solutionwas washed with water and brine and concentrated under reduced pressure.The residue thus obtained was purified by silica gel chromatography(hexane:ethyl acetate=2:1) and crystallized from ether, whereby thetitle compound (17 mg, 55%) was obtained as a solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.64 (2H, m), 2.02 (2H, m), 3.33 (2H, m),3.98 (1H, m), 4.08 (2H, m), 6.11 (1H, s), 6.92 (1H, m), 7.02 (1H, m),7.42 (2H, d, J=8.8 Hz), 7.45 (1H, m), 7.53 (1H, s), 7.58 (2H, d, J=8.8Hz), 8.05 (1H, s).

MS m/z: 513 (M⁺+H).

IR (ATR) cm⁻¹: 3359, 1589, 1495, 1317, 1234, 1081, 829.

mp: 146-148° C.

FAB-MS: 513.0588 (Calcd for C₂₃H₂₁Cl₂F₂N₂O₃S: 513.0618).

Referential Example 50 (3,6-Dichloropyridin-2-yl)(pyridine-4-yl)methanol

Under stirring at −78° C., tert-butyl lithium (1.51M pentane solution:4.6 ml) was added dropwise to a solution of 2,5-dichloropyridine (1.02g, 6.89 mmol) in ether (20 ml). After stirring at −78° C. for 2 hours,pyridin-4-carbaldehyde (0.65 ml, 6.89 mmol) was added to the reactionmixture. The resulting mixture was stirred at −78° C. for 1 hour. Waterwas added to the reaction mixture and the temperature was raised to roomtemperature. The mixture was extracted with methylene chloride. Theextract was dried over anhydrous sodium sulfate and filtered. Thefiltrate was then concentrated under reduced pressure. The residue thusobtained was subjected to chromatography on a silica gel column. Afraction obtained from the eluate with methanol:methylene chloride(1:50) was concentrated under reduced pressure. The solid thus obtainedwas washed with ether and collected by filtration, whereby the titlecompound (819 mg, 3.21 mmol, 47%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 4.64 (1H, br d, J=6.3 Hz), 6.00 (1H, br d,J=6.3 Hz), 7.27 (1H, d, J=8.6 Hz), 7.31 (2H, d, J=5.8 Hz), 7.67 (1H, d,J=8.6 Hz), 8.57 (2H, d, J=5.8 Hz).

MS (m/z): 254 (M⁺).

Example 4053,6-Dichloro-2-[(4-chlorophenylsulfonyl)(pyridine-4-yl)methyl]pyridine

Triethylamine (208 μl, 1.89 mmol) and thionyl chloride (138 μl, 1.89mmol) were added to a solution of(3,6-dichloropyridin-2-yl)(pyridin-4-yl)methanol (161 mg, 0.631 mmol) inmethylene chloride (10 ml). After stirring at room temperature for 4hours, the reaction mixture was concentrated under reduced pressure.Ethyl acetate was added to the residue thus obtained. The resultingmixture was washed successively with a saturated aqueous solution ofsodium bicarbonate and brine, and dried over anhydrous sodium sulfate.After filtration, the filtrate was concentrated under reduced pressure.The residue thus obtained was dissolved in acetonitrile (10 ml),followed by the addition of 4-chlorobenzenethiol (137 mg, 0.947 mmol)and potassium carbonate (131 mg, 0.947 mmol). Under nitrogen atmosphere,the reaction mixture was stirred at room temperature for 2 days and thenat 60° C. for 4 days. The reaction mixture was cooled to roomtemperature and then, concentrated under reduced pressure. Ethyl acetatewas added to the residue thus obtained. The mixture was washedsuccessively with water and brine, dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash chromatography. A fractionobtained from the eluate with 40% ethyl acetate/hexane was concentratedunder reduced pressure. The residue thus obtained was dissolved inmethanol (10 ml) and to the resulting solution, were added a 30% aqueoushydrogen peroxide solution and hexaammonium heptamolybdate tetrahydrate(73 mg). The reaction mixture was stirred at room temperature for 5hours. Methanol was distilled off under reduced pressure. A saturatedaqueous solution of sodium bicarbonate was added to the concentratedsolution thus obtained, followed by extraction with methylene chloride.The organic layer was dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated under reduced pressure. The residue thusobtained was subjected to flash chromatography. A fraction obtained fromthe eluate with methanol:methylene chloride (=1:80) was concentratedunder reduced pressure, whereby the title compound (49 mg, 0.118 mmol,19%) was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.08 (1H, s), 7.31 (1H, d, J=8.3 Hz), 7.41(2H, d, J=8.8 Hz), 7.45 (2H, d, J=6.0 Hz), 7.51 (2H, d, J=8.8 Hz), 7.69(1H, d, J=8.3 Hz), 8.58 (2H, d, J=6.0 Hz).

IR (ATR) ν cm⁻¹: 3068, 2923, 1594, 1562, 1475, 1415, 1394, 1313, 1280,1213, 1184, 1132, 1089, 1035, 1012, 993, 838, 813, 784, 744, 703, 595,572, 536, 485, 458.

MS (m/z): 413, 415 (M⁺+H).

Example 4062-[1-(4-Chlorophenylsulfonyl)-1-(2,5-difluorophenyl)ethyl]-5-methylpyridine

Under ice cooling, a solution of the2-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-5-methylpyridine(52 mg, 0.132 mmol), which had been obtained in Example 137, inN,N-dimethylformamide (5 ml) was added dropwise to a suspension ofsodium hydride (a 60% oil dispersion, 30 mg, 0.75 mmol) inN,N-dimethylformamide (5 ml). The reaction mixture was stirred for 15minutes under ice cooling, and then, methyl iodide (12 μl, 0.198 mmol)was added. After stirring at room temperature for 1 hour, water wasadded to the reaction mixture under ice cooling, followed byconcentration under reduced pressure. Water was added to the residue,followed by extraction with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was subjected to chromatography on a silica gel column. Afraction obtained from the eluate with hexane:ethyl acetate (=8:1) wasconcentrated under reduced pressure. The residue thus obtained wassolidified with hexane and collected by filtration, whereby the titlecompound (50 mg, 0.122 mmol, 93%) was obtained as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ: 2.14 (3H, s), 2.33 (3H, s), 6.80-7.10 (2H,m), 7.23-7.34 (4H, m), 7.39-7.51 (2H, m), 7.88-8.00 (1H, m), 8.15 (1H,s).

MS (m/z): 408 (M⁺+H).

Example 4073,6-Dichloro-2-[(6-chloropyridin-3-ylthio)(pyridine-4-yl)methyl]pyridine

A 1N aqueous solution of sodium hydroxide (7 ml) was added to a solutionof the S-(6-chloro-3-pyridyl) O-ethyl dithiocarbonate (164 mg, 0.70mmol) obtained in Referential Example 33 in ethanol (7 ml) and themixture was stirred at 80° C. for 3 hours. After cooling to roomtemperature, 1N hydrochloric acid was added to the reaction mixture. Themixture was extracted with dichloromethane. The organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure, whereby 6-chloro-3-pyridinethiolwas obtained as a yellow solid.

Triethylamine (0.167 ml, 1.20 mmol) and then, methanesulfonyl chloride(0.07 ml, 0.90 mmol) were added to a solution of the(3,6-dichloropyridin-2-yl)(pyridin-4-yl)methanol (153 mg, 0.60 mmol),which had been obtained in Referential Example 50, in dichloromethane (3ml). The resulting mixture was stirred at room temperature for 2 hours.The reaction mixture was washed with a saturated aqueous solution ofsodium bicarbonate. The organic layer was then dried over anhydroussodium sulfate and filtered. The filtrate was concentrated under reducedpressure.

A solution of 6-chloro-3-pyridinethiol in N,N-dimethylformamide (2 ml)and potassium carbonate (100 mg, 0.72 mmol) were successively added to asolution of the resulting residue in N,N-dimethylformamide (3 ml). Theresulting mixture was stirred at room temperature for 18 hours. Ethylacetate was added to the reaction mixture. After washing with asaturated aqueous solution of sodium bicarbonate, the organic layer wasdried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography. A fraction obtained fromthe elution portion with hexane:ethyl acetate=7:3 was concentrated underreduced pressure, whereby the title compound (83 mg, 0.22 mmol, 36%) wasobtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 5.69 (1H, s), 7.20 (1H, d, J=8.3 Hz), 7.24(1H, d, J=8.3 Hz), 7.35 (2H, d, J=6.1 Hz), 7.52 (1H, dd, J=8.3, 2.4 Hz),7.62 (1H, d, J=8.3 Hz), 8.32 (1H, d, J=2.4 Hz), 8.55 (2H, d, J=6.1 Hz).

MS m/z: 382 (M⁺+H).

Example 4083,6-Dichloro-2-[(6-chloropyridin-3-ylsulfonyl)(pyridin-4-yl)methyl]pyridine(Compound A) and3,6-dichloro-2-[(6-chloropyridin-3-ylsulfinyl)(pyridine-4-yl)methyl]pyridine(Compound B (Isomer A) and Compound B (Isomer B))

Compound A Compound B

A 31% aqueous hydrogen peroxide solution (2 ml) and hexaammoniumheptamolybdate tetrahydrate (30 mg) were added to a solution of3,6-dichloro-2-[(6-chloropyridin-3-ylthio)(pyridin-4-yl)methyl]pyridine(82 mg, 0.24 mmol) in methanol (4 ml). The resulting mixture was stirredat room temperature for 2 hours. Ethyl acetate was added to the reactionmixture. After washing with a saturated aqueous solution of sodiumbicarbonate, the organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated under reduced pressure. Theresidue was subjected to flash chromatography on a silica gel column. Afraction obtained from the elution portion with hexane:ethyl acetate=3:2was concentrated under reduced pressure, whereby the title compound A(41 mg, 0.098 mmol, 46%) was obtained. A fraction obtained from theelution portion with hexane:ethyl acetate=1:1 was concentrated underreduced pressure, whereby the title compound B (isomer A) (low polarity)(8 mg, 0.020 mmol, 9%) and the title compound B (isomer B) (highpolarity) (8 mg, 0.020 mmol, 9%) were obtained, respectively each as awhite solid.

Compound A

¹H-NMR (400 MHz, CDCl₃) δ: 6.11 (1H, s), 7.35 (1H, d, J=8.3 Hz), 7.36(2H, d, J=6.1 Hz), 7.40 (1H, d, J=8.3 Hz), 7.73 (1H, d, J=8.3 Hz), 7.78(1H, dd, J=8.3, 2.4 Hz), 8.48 (1H, d, J=2.4 Hz), 8.61 (2H, d, J=6.1 Hz).

MS m/z: 414 (M⁺+H).

Compound B (Isomer A)

¹H-NMR (400 MHz, CDCl₃) δ: 5.54 (1H, s), 6.99 (2H, d, J=6.1 Hz), 7.27(1H, d, J=8.3 Hz), 7.37 (1H, d, J=8.3 Hz), 7.55 (1H, dd, J=8.3, 2.2 Hz),7.73 (1H, d, J=8.3 Hz), 8.47 (1H, d, J=2.2 Hz), 8.51 (2H, d, J=6.1 Hz).

MS m/z: 398 (M⁺+H).

Compound B (Isomer B)

¹H-NMR (400 MHz, CDCl₃) δ: 5.40 (1H, s), 7.26 (1H, d, J=8.5 Hz), 7.42(1H, d, J=8.3 Hz), 7.53 (2H, d, J=6.1 Hz), 7.57 (1H, d, J=8.5 Hz), 7.96(1H, dd, J=8.3, 2.4 Hz), 8.34 (1H, d, J=2.4 Hz), 8.68 (2H, d, J=6.1 Hz).

MS m/z: 398 (M⁺+H).

Example 4092-[[(3-Chloropyridin-4-yl)(2,5-difluorophenyl)methyl]sulfonyl]pyrimidine

Triethylamine (0.112 ml, 0.80 mmol) and methanesulfonyl chloride (0.046ml, 0.60 mmol) were added successively to a solution of the3-chloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (102 mg, 0.40mmol), which had been obtained in Referential Example 48, indichloromethane (4 ml) at 0° C. The resulting mixture was stirred atroom temperature for 17 hours. After washing with a saturated aqueoussolution of sodium bicarbonate, the organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure.

To a solution of the resulting residue in N,N-dimethylformamide (4 ml)were added 2-pyrimidinethiol (45 mg, 0.40 mmol) and then, potassiumcarbonate (83 mg, 0.60 mmol) and the mixture was stirred at roomtemperature for 23 hours. Ethyl acetate was added to the reactionmixture. After washing with water, the organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure.

To a solution of the resulting residue in dichloromethane (4 ml) wasadded 3-chloroperbenzoic acid (purity: 65% or greater) (212 mg, 0.80mmol) at 0° C. and the resulting mixture was stirred at room temperaturefor 3 hours. After washing with a 1N aqueous solution of sodiumhydroxide, the organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel chromatography.A fraction obtained from the elution portion with hexane:ethylacetate=2:3 was concentrated under reduced pressure, whereby the titlecompound (19 mg, 0.049 mmol, 12%) was obtained as a colorless foam.

¹H-NMR (400 MHz, CDCl₃) δ: 6.26 (1H, s), 6.93-7.13 (3H, m), 7.50-7.56(1H, m), 8.01-8.08 (1H, m), 8.13 (1H, d, J=5.1 Hz), 8.48 (1H, d, J=2.2Hz), 8.60 (1H, s), 8.66 (1H, d, J=5.1 Hz).

MS m/z: 382 (M⁺+H).

Test Example

Cell-based assay for screening of a compound which inhibits productionor secretion of β-amyloid protein E35 cells which were established bytransfecting APP751 gene which is a wild type human β-amyloid proteinprecursor into human glioma cells (H4 cells), were used to analyzeinhibitory activity of a compound against β-amyloid production. Theamount of β protein (Aβ) secreted in a culture medium was measured bythe sandwich enzyme-linked immunosorbent assay.

E35 cells were seeded in Dulbecco's Modified Eagle's Medium containing10% inactivated fetal bovine serum on 96-well plates and cultured inhumidified air and 5% CO₂ at 37° C. in a CO₂ incubator. Twenty-fourhours after seeding of the cells, a test compound dissolved in DMSO wasadded to the medium. The DMSO solution of the compound was prepared soas to give the final concentration of DMSO in the medium 0.05%. Thecells were cultured for additional twenty-four hours, and then thecultured medium was collected. The medium collected was applied to a96-well ELISA plate on which a monoclonal antibody 25-1, whichrecognized Aβ25-35, was immobilized, followed by the incubation at 4° C.for 16 to 20 hours. After washing with a phosphate buffer (pH 7.4), abiotinylated monoclonal antibody MA³²-40, which recognizes Aβ1-8, wasadded to the plate, and the plate was incubated at 4° C. for 2 hours.Then alkaline phosphatase-conjugated streptavidin was added to theplate. Alkaline phosphatase activity was measured by a calorimetricassay using BlouPhos (manufactured by KPL) as a substrate. An amount ofAβ in the medium was calculated using a calibration curve separatelycreated. EC₅₀ of the test compound was presented as the concentrationthat gives 50% inhibitory activity compared to the control cells whichwere not treated with the compound.

On the other hand, cytotoxicity of the compound was assayed accordingthe following. The compound was added to the cultured H4 cells and afterincubation for 72 hours, a calorimetric assay was performed usingAlamarBlue (manufactured by BIOSOURCE) and the absorbance of the wellswas measured. Concentration of the test compounds which gives 80% orless of the absorbance compared to that of the control cells was definedas the concentration at which cytotoxicity was appeared. When asignificant difference between the EC₅₀ and the concentration at whichcytotoxicity was appeared was observed, then the compound is judged asan active compound.

The results of evaluation of the compound (1) using an above-mentionedassay are shown in Table 1. Compounds exhibiting EC50 not greater than50 nM are evaluated as +++, those exhibiting EC50 ranging from 50 nM to500 nM are evaluated as ++ and those exhibiting EC50 ranging from 500 nMto 5 μM are evaluated as +. Compound Activity Example 2 (Isomer 2-B) +Example 3 ++ Example 10 ++ Example 12 + Example 14 + Example 17 +Example 27 (Compound A) ++ Example 29 ++ Example 32 ++ Example 33 +++Example 35 + Example 36 ++ Example 43 (Isomer 43-A) ++ Example 43(Isomer 43-B) ++ Example 45 +++ Example 46 ++ Example 47 +++ Example 48+++ Example 136 +++ Example 141 ++ Example 142 ++ Example 145 +++Example 287 ++ Example 288 ++ Example 330 ++ Example 331 ++ Example 334++ Example 343 +++ Example 344 +++ Example 345 +++ Example 347 +++Example 349 +++ Example 370 ++ Example 372 ++ Example 397 +++ Example399 +++ Example 402 +++ Example 404 +++

INDUSTRIAL APPLICABILITY

Compounds represented by the formula (1), salts, N-oxides and S oxidesthereof, and solvate of any one of them have an inhibitory actionagainst production or secretion of β-amyloid protein. They are thereforepharmaceutically effective for the prevention and treatment of variousdiseases such as Alzheimer disease, Down syndrome and the other diseasesassociated with amyloid deposition.

1-17. (canceled)
 18. A compound represented by the following formula(3):

wherein R¹⁵ represents a heterocyclic group which may have asubstituent, R¹⁶ represents a cyclic hydrocarbon group which may have asubstituent or a heterocyclic group which may have a substituent, R¹⁷represents pyridyl group which may have at least one substituent, R¹⁸represents a hydrogen atom or a C₁₋₆ alkyl group, and X represents —S—,—SO— or —SO₂—; or N-oxide or S-oxide of the compound; salt thereof; orsolvate of the above-described compound.
 19. The compound of claim 18,wherein X represents —SO— or —SO₂—; or N-oxide or S-oxide of thecompound; salt thereof; or solvate of the above-described compound. 20.The compound of claim 18, wherein X represents —SO₂—; or N-oxide orS-oxide of the compound; salt thereof; or solvate of the above-describedcompound.
 21. The compound of claim 18, wherein the heterocyclic grouprepresented by R¹⁵ or R¹⁶ is a 3- to 7-membered saturated or 4- to7-membered unsaturated monocyclic heterocyclic group having from 1 to 4atoms selected from nitrogen atom, oxygen atom and sulfur atom, or a 7-to 14-membered polycyclic heterocyclic group having from 1 to 4 atomsselected from nitrogen atom, oxygen atom and sulfur atom; or N-oxide orS-oxide of the compound; salt thereof; or solvate of the above-describedcompound.
 22. The compound of claim 18, wherein the cyclic hydrocarbongroup represented by R¹⁶ is a cycloalkyl group having from 3 to 7 carbonatoms, cycloalkenyl group having from 4 to 7 carbon atoms, monocyclic orpolycyclic aromatic hydrocarbon group having from 6 to 14 carbon atoms,spirohydrocarbon group having from 7 to 11 carbon atoms, crosslinkedcyclic hydrocarbon group having from 7 to 10 carbon atoms or condensedpolycyclic hydrocarbon group having from 8 to 14 carbon atoms; orN-oxide or S-oxide of the compound; salt thereof; or solvate of theabove-described compound.
 23. The compound of claim 18, wherein thesubstituent for the group represented by R¹⁵, R¹⁶, or R¹⁷ is a group-Q²⁰¹-Q²⁰²-Q²⁰³-Q²⁰⁴, Q²⁰⁵-Q²⁰⁶-Q²⁰⁷, in which represents a single bond,an alkyl group having from 1 to 6 carbon atoms, an alkenyl group havingfrom 2 to 6 carbon atoms or a heterocyclic group; Q²⁰² represents asingle bond, —O—, —NH—, —CH═—N—, —C(alkyl)═N—, —N(alkyl)- or —S—; Q²⁰³represents a single bond, —CO—, —CS—, —SO—, —SO₂— or —CONH—; Q²⁰⁴represents a single bond, an alkyl group from 1 to 6 carbon atoms, analkenyl group having from 2 to 6 carbon atoms, a cycloalkyl group, acycloalkenyl group, an aromatic hydrocarbon group or a heterocyclicgroup; Q²⁰⁵ represents a single bond, —NH— or —N(alkyl)-; Q²⁰⁶represents a single bond, —O—, —CO—, —CS—, —SO₂—, —SO— or —S—; and Q²⁰⁷represents a hydrogen atom, a halogen atom, a hydroxy group, an oxogroup, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₈ cycloalkylgroup, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group, an azide group, acyano group, an amino group, a C₁₋₆ alkylamino group, a di(C₁₋₆alkyl)amino group, a C₂₋₆ alkanoylamino group, a di(C₂₋₆ alkanoyl)aminogroup, a carboxyamino group, a C₁₋₆ alkoxycarbonylamino group, a di(C₁₋₆alkoxy)carbonylamino group, a heterocyclic group, an aromatichydrocarbon group, a cycloalkenyl group, a heterocyclic oxy group, or anaromatic hydrocarbon-oxy group (wherein, the alkyl group having from 1to 6 carbon atoms, alkenyl group having from 2 to 6 carbon atoms,cycloalkyl group, cycloalkenyl group, heterocyclic group,heterocyclic-oxy group, aromatic hydrocarbon group or aromatichydrocarbon-oxy group may be substituted with 1 to 3 substituentsselected from halogen atoms, C₁₋₆ alkyl groups, C₁₋₆ alkoxy groups, C₂₋₆alkenyl groups, carboxyamino C₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonylaminoC₁₋₆ alkyl groups, formyl group, C₂₋₆ alkanoyl groups, oxo group, nitrogroup, cyano group, azide group, amidino group, C₂₋₆ alkenyloxy groups,hydroxy group, carboxyl group, C₇₋₁₆ aralkyl groups, thioxo group, C₂₋₇alkanoyl groups, C₂₋₇ thioalkanoyl groups, thioformyl group, aminogroup, C₁₋₆ alkylamino groups, di(C₁₋₆ alkyl)amino groups, C₁₋₆alkoxycarbonyl groups, carbamoyl group, C₁₋₆ alkylcarbamoyl groups,di(C₁₋₆ alkyl)carbamoyl groups, thiocarbamoyl group, C₁₋₆alkylthiocarbamoyl groups, di(C₁₋₆ alkyl)thiocarbamoyl groups, C₁₋₆alkoxycarbamoylamino groups, C₁₋₆ alkoxycarbamoyl(C₁₋₆ alkyl)aminogroups, C₂₋₇ alkanoylamino groups, C₂₋₇ alkanoyl (C₁₋₆ alkyl)aminogroups, thio C₂₋₇ alkanoylamino groups, thio C₂₋₇ alkanoyl (C₁₋₆alkyl)amino groups, formylamino group, formyl(C₁₋₆ alkyl)amino groups,thioformylamino group, thioformyl(C₁₋₆ alkyl)amino groups, C₂₋₇alkanoyloxy groups, formyloxy group, C₁₋₆ alkoxycarbonyloxy groups,carbamoyloxy group, C₁₋₆ alkylcarbamoyloxy groups, di(C₁₋₆alkyl)carbamoyloxy groups, aminocarbonylamino group, (C₁₋₆alkyl)aminocarbonylamino groups, di(C₁₋₆ alkyl)aminocarbonylaminogroups, aminocarbonyl(C₁₋₆ alkyl)amino groups, (C₁₋₆alkyl)aminocarbonyl(C₁₋₆ alkyl)amino groups, di(C₁₋₆alkyl)aminocarbonyl(C₁₋₆ alkyl)amino groups, mercapto group, C₁₋₆alkylthio groups, C₁₋₆ alkylsulfinyl groups, C₁₋₆ alkylsulfonyl groups,aminosulfonyl group, C₁₋₆ alkylaminosulfonyl groups, di(C₁₋₆alkyl)aminosulfonyl groups, C₁₋₆ alkylsulfonylamino groups, C₁₋₆alkylsulfonyl(C₁₋₆ alkyl)amino groups, aminosulfonylamino group, C₁₋₆alkylaminosulfonylamino groups, di(C₁₋₆ alkyl)aminosulfonylamino groups,aminosulfonyl(C₁₋₆ alkyl)amino groups, C₁₋₆ alkylaminosulfonyl(C₁₋₆alkyl)amino groups, and di(C₁₋₆ alkyl)aminosulfonyl(C₁₋₆ alkyl)aminogroups; or N-oxide or S-oxide of the compound; salt thereof; or solvateof the above-described compound.
 24. The compound of claim 18, whereinR¹⁶ represents a monocyclic or polycyclic aromatic hydrocarbon grouphaving from 6 to 14 carbon atoms, or a heterocyclic group (in which, thehydrocarbon group or heterocyclic group may have 1 to 3 substituentsselected from halogen atoms, C₁₋₆ alkyl groups, C₁₋₆ alkoxy groups, C₂₋₆alkenyl groups, formyl group, C₂₋₆ alkanoyl groups, carboxyl group,carboxyamino C₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonylamino C₁₋₆ alkylgroups, oxo group, nitro group, cyano group, amidino group, C₂₋₇alkenyloxy groups, hydroxy group, thioxo group, amino group, C₁₋₆alkylamino groups, di C₁₋₆ alkylamino groups, C₁₋₆ alkoxycarbonylgroups, carbamoyl group, C₁₋₆ alkylcarbamoyl groups, di C₁₋₆alkylcarbamoyl groups, thiocarbamoyl group, C₁₋₆ alkylthiocarbamoylgroups, di C₁₋₆ alkylthiocarbamoyl groups, mercapto group, C₁₋₆alkylthio groups, C₁₋₆ alkylsulfinyl groups and C₁₋₆ alkylsulfonylgroups); and R¹⁵ represents a heterocyclic group (in which, theheterocyclic group may be substituted with a halogen atom, C₁₋₆ alkylgroup, C₁₋₆ alkoxy group, C₂₋₆ alkenyl group, C₂₋₆ alkenyloxy group,hydroxy group, carboxyl group, carboxy C₁₋₆ alkyl group, C₁₋₆alkoxycarbonyl C₁₋₆ alkyl group, C₁₋₆ alkoxycarbonyl-C₂₋₆ alkenyl group,hydroxyl C₁₋₆ alkyl group, C₆₋₁₄ aromatic hydrocarbon-sulfonyl C₁₋₆alkyl group, heterocyclic-C₁₋₆ alkylamino group, heterocyclic group,heterocyclic-C₁₋₆ alkyl group, C₆₋₁₄ aromatic hydrocarbon group, C₆₋₁₄aromatic hydrocarbon C₁₋₆ alkyl group, C₆₋₁₄ aromatic hydrocarbon thioC₁₋₆ alkyl group, azido-(C₁₋₆ alkyl) group, amino C₁₋₆ alkyl group, C₁₋₆alkylamino C₁₋₆ alkyl group, di C₁₋₆ alkylamino C₁₋₆ alkyl group,hydroxyl C₁₋₆ alkylamino C₁₋₈ alkyl group, C₁₋₆ alkoxy C₁₋₆ alkylaminoC₁₋₆ alkyl group, (hydroxy C₁₋₆ alkyl)(C₁₋₆ alkoxy C₁₋₆ alkyl)amino C₁₋₆alkyl group, C₂₋₆ alkanoylamino C₁₋₆ alkyl group, C₆₋₁₄ aromatichydrocarbon sulfonylamino C₁₋₆ alkyl group, C₁₋₆ alkoxycarbonylaminoC₁₋₆ alkyl group, carbamoylamino C₁₋₆ alkyl group, N-alkylcarbamoylaminoC₁₋₆ alkyl group, N,N-dialkylcarbamoylamino C₁₋₆ alkyl group,aminosulfonylamino C₁₋₆ alkyl group, N-alkylsulfonylamino C₁₋₆ alkylgroup, N,N-dialkylsulfonylamino C₁₋₆ alkyl group, C₆₋₁₄ aromatichydrocarbon C₁₋₆ alkylamino group, heterocyclic C₁₋₆ alkylamino group,carbamoyloxy C₁₋₆ alkyl group, N-alkylcarbamoyloxy C₁₋₆ alkyl group,N,N-dialkylcarbamoyloxy C₁₋₆ alkyl group, C₆₋₁₄ aromatichydrocarbon-C₁₋₆ alkylcarbamoyloxy C₁₋₆ alkyl group, C₁₋₆alkoxycarbonyloxy-C₁₋₆ alkyl group, C₆₋₁₄ aromatichydrocarbonoxycarbonyloxy C₁₋₆ alkyl group, C₆₋₁₄ aromatichydrocarbonsulfonylamino-C₁₋₆ alkanoylamino C₁₋₆ alkyl group, C₁₋₆alkoxycarbonylamino C₁₋₆ alkylamino group, amino C₁₋₆ alkylamino group,C₁₋₆ alkylamino C₁₋₆ alkylamino group, di(C₁₋₆ alkyl)amino C₁₋₆alkylamino group, carboxyamino C₁₋₆ alkyl group, C₁₋₆alkoxycarbonylamino C₁₋₆ alkyl group, C₁₋₆ alkylsulfonylamino C₁₋₆ alkylgroup, amino C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl group, N—C₁₋₆ alkylaminoC₁₋₆ alkylcarbonylamino C₁₋₆ alkyl group, N,N-di C₁₋₆ alkylamino C₁₋₆alkylcarbonylamino C₁₋₆ alkyl group, heterocyclic carbonyl group,heterocyclic carbonylamino group, C₆₋₁₄ aromatic hydrocarboncarbonylgroup, C₆₋₁₄ aromatic carbonylamino group, heterocyclic C₁₋₆alkylcarbonylamino C₁₋₆ alkyl group, heterocyclic C₂₋₆alkenylcarbonylamino C₁₋₆ alkyl group, C₆₋₁₄ aromatichydrocarbonalkenylcarbonylamino C₁₋₆ alkyl group, C₆₋₁₄ aromatichydrocarboncarbonylamino C₁₋₆ alkyl group, heterocyclic carbonylaminoC₁₋₆ alkyl group, C₁₋₆ alkoxyoxalylamino C₁₋₆ alkyl group, carbamoylgroup, N—C₁₋₆ alkylcarbamoyl group, N,N-di C₁₋₆ alkylcarbamoyl group,C₁₋₆ alkyl-C₃₋₈ cycloalkylcarbamoyl group, C₃₋₈ cycloalkyl-C₁₋₆alkylcarbamoyl group, heterocyclic carbamoyl group, C₁₋₆ aromaticcarbamoyl group, heterocyclic carbonylhydrazonomethyl group, C₆₋₁₄aromatic hydrocarboncarbonylhydrazonomethyl group, C₁₋₆ alkylthio C₁₋₆alkylcarbamoyl group, C₁₋₆ alkylsulfinyl C₁₋₆ alkylcarbamoyl group, C₁₋₆alkylsulfonyl C₁₋₆ alkylcarbamoyl group, hydroxyaminocarbonyl group,hydrazinocarbonyl group or N—C₁₋₆ alkylhydrazinocarbonyl group,thioformylamino-C₆₋₁₄ aromatic hydrocarbon-thiocarbonylamino C₁₋₆ alkylgroup, thioformyl-(C₁₋₆ alkylamino-C₆₋₁₄ aromatichydrocarbon-thiocarbonylamino C₁₋₆ alkyl group, formylamino-C₆₋₁₄aromatic hydrocarbon-carbonylamino C₁₋₆ alkyl group, formyl-C₁₋₆alkylamino-C₆₋₁₄ aromatic hydrocarbon-carbonylamino C₁₋₆ alkyl group,C₁₋₆ alkanoyl-heterocycle-carbonylamino C₁₋₆ alkyl group, di(C₂₋₆alkanoyl)amino(C₁₋₆ alkyl) group, di(C₁₋₆ alkoxycarbonyl)amino C₁₋₆alkyl group, C₁₋₆ alkyl-heterocycle-carbonyl group, C₃₋₇ cycloalkyl C₁₋₆alkylaminocarbonyl group, C₁₋₆ alkoxyaminocarbonyl group, (hydroxy)(C₁₋₆alkyl)aminocarbonyl group, (C₁₋₆ alkoxy)(C₁₋₆ alkyl)aminocarbonyl group,N′—C₁₋₆ alkylhydrazinocarbonyl group, N′,N′-di C₁₋₆alkylhydrazinocarbonyl group, N,N′-di C₁₋₆ alkylhydrazinocarbonyl group,N,N′,N′-tri C₁₋₆ alkylhydrazinocarbonyl group,N′-(heterocycle-carbonyl)-hydrazinocarbonyl group, formyl group,hydroxyimino group, C₁₋₆ alkoxyimino group, bis(C₁₋₆ alkoxy C₁₋₆alkyl)amino C₁₋₆ alkyl group, hydroxy-C₁₋₆ alkyl-heterocyclic group,C₁₋₆ alkoxy-C₁₋₆ alkyl-heterocyclic group, C₁₋₆ alkoxycarbonylamino C₁₋₆alkyl-heterocyclic group, amino C₁₋₆ alkyl-heterocyclic group, N—C₁₋₆alkylamino C₁₋₆ alkyl-heterocyclic group, N,N-di C₁₋₆ alkylamino C₁₋₆alkyl-heterocyclic group, hydroxy-heterocyclic group, C₁₋₆alkoxy-heterocyclic group, carboxy-C₂₋₅ alkenyl group, or oxo group(wherein, the above-described C₆₋₁₄ aromatic hydrocarbon group orheterocyclic group may be substituted with a halogen atom, C₁₋₆ alkylgroup, C₁₋₆ alkoxy group, C₂₋₆ alkenyl group, formyl group, C₂₋₆alkanoyl group, carboxyl group, carboxyamino C₁₋₆ alkyl group, C₁₋₆alkoxycarbonylamino C₁₋₆ alkyl group, oxo group, nitro group, cyanogroup, amidino group, C₂₋₆ alkenyloxy group, hydroxy group, thioxogroup, amino group, C₁₋₆ alkylamino group, di C₁₋₆ alkylamino group,amino C₁₋₆ alkyl group, C₁₋₆ alkoxycarbonyl group, carbamoyl group, C₁₋₆alkylcarbamoyl group, di C₁₋₆ alkylcarbamoyl group, thiocarbamoyl group,C₁₋₆ alkylthiocarbamoyl group, di(C₁₋₆ alkyl)thiocarbamoyl group, C₂₋₇alkanoylamino group, C₂₋₇ alkanoyl(C₁₋₆ alkyl)amino group, thio(C₂₋₇alkanoyl)amino group, thio(C₂₋₇ alkanoyl)(C₁₋₆ alkyl)amino group,formylamino group, formyl(C₁₋₆ alkyl)amino group, thioformylamino group,thioformyl(C₁₋₆ alkyl)amino group, C₂₋₇ alkanoyloxy group, formyloxygroup, mercapto group, C₁₋₆ alkylthio group, C₁₋₆ alkylsulfinyl group,C₁₋₆ alkylsulfonyl group, aminosulfonyl group, C₁₋₆ alkylaminosulfonylgroup, di(C₁₋₆ alkyl)aminosulfonyl group, C₁₋₆ alkylsulfonylamino groupor C₁₋₆ alkylsulfonyl(C₁₋₆ alkyl)amino group); or N-oxide or S-oxide ofthe compound; salt thereof, or solvate of the above-described compound.25. A medicament comprising, as an active ingredient, a compound ofclaim 18, or N-oxide or S-oxide of the compound, salt thereof, orsolvate of the above-described compound.
 26. The medicament of claim 25,which is used for prevention or treatment of a disease resulting fromabnormal production or secretion of β-amyloid.
 27. The medicament ofclaim 25, which is used for prevention or treatment of Alzheimer diseaseor Down syndrome.
 28. A pharmaceutical composition comprising a compoundof claim 18, or N-oxide or S-oxide of the compound, salt thereof, orsolvate of the above-described compound; and a pharmaceuticallyacceptable carrier.
 29. A method to treat a disease resulting fromabnormal production or secretion of β-amyloid, which comprisesadministering to a subject an effective amount of a compound of claim18, or N-oxide or S-oxide of the compound, salt thereof, or solvate ofthe above-described compound.
 30. The method of claim 29, wherein thedisease resulting from abnormal production or secretion of β-amyloidprotein is Alzheimer disease or Down syndrome.